Piperidine derivatives as human papilloma virus inhibitors

ABSTRACT

HPV inhibitors with formula (I) where G 1  represents a hydrocarbonated bond or chain possibly substituted by one or two alkyl groups, G 2  represents a group (see formula Ia+Ib) or R represents a hydrogen, an alkyl, halogenoalkyl, or a prodrug radical such as carbamate, acetyl or dialkylaminomethyl, G represents a bond or a hydrocarbonated chain possibly substituted by one or two alkyls, W represents an oxygen or sulphur, R 1  and R 2  each represent a group chosen from among hydrogen, halogen, hydroxyl, thio, alkoxy, halogenoalkoxy, alkylthio, halogenoalkylthio, amino, monoalkylamino, dialkylamino, cycloalkyl, alkyl or halogenoalkyl, R 3  represents an acid or a prodrug radical of the acid function or a bioisostere of the acid function, A represents an aryl, cycloalkyl, cycloalkenyl or a heterocycle, each possibly substituted, and B represents an aryl or a heterocycle with 6 chains, each possibly substituted, and pharmaceutically acceptable salts.

The present invention relates to novel antiviral compounds directedagainst the papilloma virus, to pharmaceutical compositions containingthem, to their preparation method and synthesis intermediates as well asto their use for treating or preventing an infection by the papillomavirus.

The papilloma viruses are non-encased viruses, the genome of which isformed by double strand DNA of about 8 kb. They are very widespread innature and cause epithelial lesions in human as well as in many animalsincluding rabbits, horses, dogs, and bovine species. More than a hundredhuman papilloma viruses (HPV) have been described. They are classifieddepending on their infection sites. About 30 HVP have been isolated fromanogenital mucosas (cervix uteri, vagina, valva, penis, anus, rectum).The other HPVs are associated with skin lesions. The HPVs with cutaneoustropism include i.a., HPV1, HPV2, HPV3, HPV4, HPV5, HPV7, HPV8, HPV9,HPV10, HPV12, HPV14, HPV15, HPV17, HPV19, HPV20, HPV21, HPV22, HPV23,HPV24, HPV25, HPV26, HPV27, HPV28, HPV29, HPV38, HPV41, HPV47, HPV49.They are associated with lesions such as warts (verruca vulgaris,verruca plantaris, myrmecia wart, surface wart, verruca plana . . . )and diseases such as epidermo-dysplasia verruciformis.

The mucogenital type HPVs are involved in laryngeal and anogenitaldiseases including certain cancers. They are often classified as highrisk HPVs and low risk HPVs, with reference to the type of lesions withwhich they are associated. The low risk HPVs include, i.a., HPV6, HPV11,HPV13, HPV32, HPV34, HPV40, HPV42, HPV43, HPV44, HPV53, HPV54, HPV55,HPV57, HPV58, HPV74, HPV91.

The low risk HPVs are associated with benign lesions such as condylomas(genital warts such as acuminated condylomas and plane condylomas),laryngeal, conjunctive or buccal papillomas or other epithelial lesionssuch as intra-epithelial neoplasias of low grade or recurrentrespiratory papillomatoses, and more rarely bowenoid papuloses or highgrade intra-epithelial neoplasias or carcinomas. High risk HPVs includei.a., HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52,HPV56, HPV59, HPV61, HPV62, HPV66, HPV67, HPV68, HPV72. They areinvolved in low grade intra-epithelial lesions which may develop intohigher grade lesions right up to cancers, in particular cervix utericancer and other anogenital cancers.

Genital infections by HPVs are the most frequent sexually transmittedinfections in the world, including in the developed countries with morethan 20 million people infected in the United States. Prevalence of HPVinfections varies from 3-42% depending on the countries and affects10-20% of the sexually active population in industrialized countries. Inpart of this population, the infection persists and may lead to cancersin the case of high risk HPVs.

The prevalence of genital warts (condylomas) is estimated to be 1-2% inthe sexually active population of industrialized countries, i.e. about3,500,000 new cases every year in these countries and 28,000,000worldwide. Genital warts may be found on parts of the body comprisingthe anus, vulva, vagina, cervix uteri and penis or peripheral bodiesthereto.

Treatments of genital warts are based on several strategies, fromphysical destruction (cryotherapy, CO₂ laser, electro-surgery, surgicalexcision), application of cytotoxic agents (TCA, podophyllin, podofilox)right up to the application of immuno-modulator agents (interferon,imiquimod). However, none of these methods completely eliminates all theviral particles, and significant rates of recurrence, accompanied bysevere secondary effects are observed with present therapeuticstrategies. This reinforces a need for new strategies for controlling oreliminating infections by papilloma viruses.

Unlike what exists in the treatment of other viral diseases, such asthose caused by HIV, herpes viruses or influenza viruses, to this daythere is no antiviral treatment which specifically targets viralpathogens which the papilloma viruses are.

The papilloma viruses infect multistratified epitheliums and their viralcycle is closely related to organogenesis of theses organs and todifferentiation of keratinocytes. After infection, the viral genome ispresent and replicated in a small number in basal cells of theepithelium. As the cells gradually differentiate, the expression of theviral genes and the number of copies of the viral genome increase untilexpression of the genes of the viral capsid and formation of infectiousvirions in totally differentiated keratinocytes.

The genome of HPVs potentially codes for about ten proteins. Theearliest expressed proteins, E1 and E2, are involved in the replicationof the viral genome and the regulation of the expression of the viralgenes.

The other early proteins of these viruses (E4, E5, E6, E7) havefunctions in relationship with cell proliferation or roles which are notyet completely explained. The existence of E3 and E8 proteins is stilluncertain. Late proteins L1 and L2 are those which form the viralcapsid.

The only 2 viral proteins required and sufficient for replicating HPVsare E1 and E2. They are capable of forming an E1/E2 complex and ofbinding on the replication origin (Ori) of the HPVs, a sequencecontained in the viral genome and bearing close sites recognized by E1and by E2. E2 is capable of binding with very high affinity to the E2sites whereas E1, alone, does not have very high affinity for E1 sites.

The interaction between E1 and E2 increases binding of E1 on Ori bycooperative binding to DNA. Once it is bound to DNA, E1 no longerinteracts with E2 but forms a hexamer. The helicase and ATPaseactivities of E1 allow unfolding of the viral DNA which is thenreplicated by the cell replication mechanism.

The inventors have sought to develop small molecules which inhibitreplication of HPVs, preferably with a low risk, by notably interferingwith the formation of the complex between the E1 and E2 proteins.

A solution was found by elaborating novel derivatives.

The object of the present invention is these novel derivatives, theirsynthesis, as well as their use in pharmaceutical compositions capableof being used in preventing and treating pathologies related toinhibition of HPV replication, such as for example, HPV1, HPV2, HPV3,HPV4, HPV5, HPV7, HPV8, HPV9, HPV10, HPV12, HPV14, HPV15, HPV17, HPV19,HPV20, HPV21, HPV22, HPV23, HPV24, HPV25, HPV26, HPV27, HPV28, HPV29,HPV38, HPV41, HPV47, HPV49, HPV6, HPV11, HPV13, HPV32, HPV34, HPV40,HPV42, HPV43, HPV44, HPV53, HPV54, HPV55, HPV57, HPV58, HPV74, HPV91,HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56,HPV59, HPV61, HPV62, HPV66, HPV67, HPV68, HPV72 preferably low risk HPVssuch as HPV6, HPV11, HPV13, HPV32, HPV34, HPV40, HPV42, HPV43, HPV44,HPV53, HPV54, HPV55, HPV57, HPV58, HPV74, HPV91.

The novel derivatives, objects of the present invention, are activeagainst the papilloma virus. They are also capable of inhibiting E1/E2interaction.

Within the scope of the present invention, the following definitions areprovided:

“Alkyl” or “Alk” means a monovalent or divalent, linear or branched,saturated hydrocarbon chain, comprising 1-6 carbon atoms such as themethyl, ethyl, propyl, isopropyl, tertbutyl, methylene, ethylene,propylene group . . .

“Acyl” means a —COR group wherein R is an alkyl group as defined earlieror a phenyl group, for example an acetyl, ethylcarbonyl, benzoyl group .. .

“Acylamino” means a —NHC(O)R group wherein R is an alkyl group asdefined earlier.

“Acylaminoalkyl” means a -AlkNHC(O)R group wherein Alk and R are alkylgroups as defined earlier.

“Alkoxy” means a —OAlk group wherein Alk is an alkyl group as definedearlier. Alkoxy comprises for example methoxy, ethoxy, n-propyloxy,tert-butyloxy, . . .

“Aryl” means an aromatic monocyclic or bicyclic system comprising 4-10carbon atoms, it being understood that in the case of a bicyclic system,one of the rings has an aromatic character and the other ring isaromatic or unsaturated. Aryl comprises for example phenyl, naphthyl,indenyl, benzocyclobutenyl goups, . . .

“Heterocycle” means a saturated, unsaturated or aromatic, fused,spiro-fused or bridged monocyclic or bicyclic system with 3-12 members,comprising 1-4 heteroatoms, either identical or different, selected fromoxygen, sulfur and nitrogen, and possibly containing 1 or 2 oxo orthioxo groups, it being understood that in the case of a bicyclicsystem, one of the rings may have an aromatic character and the otherring is aromatic or unsaturated. Heterocycle comprises for example thepiperidyl, piperazyl, furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,pyridyl, pyrimidyl, pyrazinyl, pyradizinyl, benzofuryl, benzothienyl,indolyl, quinolyl, isoquinolyl, benzodioxolyl, benzodioxinyl,benzo[1,2,5]thiadiazolyl, benzo[1,2,5]oxadiazolyl, [1,2,3]triazolyl,[1,2,4]triazolyl groups, . . .

“Alkylthio” means a —SAlk group wherein Alk is an alkyl group as definedearlier. Alkylthio comprises for example methylthio, ethylthio,isopropylthio, heptylthio, . . .

“Arylalkyl” means a -Alk-Ar group wherein Alk represents an alkyl groupas defined earlier and Ar represents an aryl group as defined earlier.

“Halogen atom” means a fluorine, bromine, chlorine or iodine atom.

“Cycloalkyl” means a saturated, fused or bridged monocyclic or bicyclicsystem comprising 3-12 carbon atoms such as the cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, decalinyl,norbornyl group, . . .

“Cycloalkenyl” means an unsatured fused or bridged monocyclic orbicyclic system comprising 3-12 carbon atoms such as the cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl group, . . .

“Monoalkylamino” means a —NHAlk group wherein Alk is an alkyl group asdefined earlier.

“Dialkylamino” means a —NAlkAlk′ group wherein Alk and Alk′ eachrepresent independently of each other an alkyl group as defined earlier.

“Monoalkylamide” means a —C(O)NHAlk group wherein Alk is an alkyl groupas defined earlier.

“Dialkylamide” means a —C(O)NAlkAlk′ group wherein Alk and Alk′ eachrepresent independently of each other an alkyl group as defined earlier.

“N-cycloalkyl” means a cycloalkyl radical as defined earlier comprisinga nitrogen atom, bound to the remainder of the molecule through thisatom. N-binding sequence of their atoms or in the arrangement of theiratoms in space. Isomers which differ in the arrangement of their atomsin space are designated by “stereoisomers”. Stereoisomers which are notmirror images of each other are designated by “diastereoisomers” andstereoisomers which are non-superposable images in a mirror aredesignated by “enantiomers” or optical isomers. “Stereoisomers” refer toracemates, enantiomers and diastereoisomers.

“Pharmaceutically acceptable” means that which is generally secure,non-toxic, and which is not biologically undesirable, both forveterinary use and for human pharmaceutical use.

“Pharmaceutical acceptable salts” of a compound means salts which arepharmaceutically acceptable as defined herein and which have the desiredpharmacological activity of the parent compound. It should be understoodthat all references to pharmaceutically acceptable salts comprise thesolvent addition forms (solvates) or crystalline forms (polymorphousforms) such as defined herein, of the same acid or base addition salts.A review of pharmaceutically acceptable salts is notably described in J.Pharm. Sci., 1977, 66, 1-19.

“Pharmaceutically acceptable acids” mean non-toxic acid salts derivedfrom organic or mineral acids. Among pharmaceutically acceptable acids,mention may be made in a non-limiting way, of hydrochloric, hydrobromic,sulfuric, phosphonic, nitric, acetic, trifluoroacetic, lactic, pyruvic,malonic, succinic, glutaric, fumaric, tartaric, maleic, citric,ascorbic, oxalic, methane-sulfonic, camphoric, benzoic, toluenesulfonicacids, . . .

“Pharmaceutically acceptable bases” mean non-toxic basic salts derivedfrom organic or mineral bases, formed when an acidic proton present inthe parent compound is replaced by a metal ion or is coordinated to anorganic base. Among pharmaceutically acceptable bases, mention may bemade in a non-limiting way to sodium hydroxide, potassium hydroxide,lithium hydroxide, calcium hydroxide, triethylamine, tertbutylamine,diethylaminoethanol, ethanolamine, ethylenediamine,dibenzylethylenediamine, piperidine, pyrrolidine, morpholine,piperazine, benzylamine, arginine, lysine, histidine, glucosamine,quaternary ammonium hydroxides, . . .

By “prodrug” is meant a chemical derivative of the compound, object ofthe present invention, which generates in vivo said compound by aspontaneous chemical reaction with the physiological medium, notably byan enzymatic reaction, a photolysis and/or a metabolic reaction.

By “prodrug radical of the acid function” is meant a labile functionalgroup which will generate in vivo an acid function upon being separatedfrom the compound, object of the present invention, by a spontaneouschemical reaction with the physiological medium, notably by enzymaticreaction, photolysis and/or metabolic reaction. The prodrug radicalswith an acid function notably comprise ester, pivoyloxymethyl,acetoxymethyl, phthalidyl, indanyl, methoxymethyl or5-R-2-oxo-1,3-dioxolen-4-ylmethyl groups. Other examples are describedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems”, Vol.14, A.C.S. Symposium Series, American Chemical Society (1975) andcycloalkyl for example comprises the piperid-1-yl or pyrrolid-1-ylgroup.

“N-cycloalkenyl” means a cycloalkenyl radical as defined earlier,comprising a nitrogen atom, bound to the remainder of the moleculethrough this atom. N-cycloalkenyl for example comprises thetetrahydropyridin-1-yl group.

“Haloalkyl” means a linear or branched saturated hydrocarbon chaincomprising 1-6 carbon atoms and substituted with 1-6 halogen atoms suchas the trifluoromethyl, 2,2,2-trifluoroethyl group, . . .

“Haloalkoxy” means a branched or linear saturated hydrocarbon chaincomprising 1-6 carbon atoms and substituted with 1-6 halogen atoms, saidchain being bound to the compound through an oxygen atom, such as thetrifluoromethoxy, 2,2,2-trifluoroethoxy group, . . .

“Haloalkylthio” means a linear or branched saturated hydrocarbon chaincomprising 1-6 carbon atoms and substituted with 1-6 halogen atoms, saidchain being attached through a sulfur atom, such as thetrifluoromethylthio group, . . .

“Protective Group” or “protection group” means the group whichselectively blocks the reactive site in a multifunctional compound sothat a chemical reaction may be selectively carried out at anothernon-protected reactive site, in the sense conventionally associated withthe latter in synthesis chemistry.

“Isomerism” means compounds which have identical molecular formulae butwhich differ by nature or in the “Bioreversible Carriers in Drug Design:Theory and Application”, edited by E. B. Roche, Pergamon Press: NewYork, 14-21 (1987).

In the present patent application, chemical compounds are namedaccording to the IUPAC (The International Union of Pure and AppliedChemistry) nomenclature.

The object of the present invention is compounds of formula (I):

as well as their stereoisomers,wherein:G₁ represents a bond or a saturated or unsaturated, branched or linearhydrocarbon chain comprising 1-4 carbon atoms, optionally substitutedwith one or two alkyl groups, preferably identical,

G₂ represents a

group wherein:

-   -   R represents hydrogen atom, an alkyl, haloalkyl group, or a        prodrug radical such as a carbamate, acetyl, dialkylaminomethyl        or —CH₂—O—CO-Alk,    -   G represents a bond or a saturated or unsaturated, linear or        branched hydrocarbon chain comprising 1-4 carbon atoms,        optionally substituted with one or two alkyl groups, preferably        identical,    -   W represents an oxygen, sulfur atom or NH,        R₁ and R₂ either identical or different, each represent a group        selected from a hydrogen atom, a halogen atom, a hydroxyl, thio,        alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino,        monoalkylamino, dialkylamino, cycloalkyl, alkyl or haloalkyl        group,        R₃ represents an acid group or a prodrug radical of the acid        function such as an ester, or else a bioisoster of the acid        function such as a tetrazole, phosphonate, phosphonamide,        sulfonate or sulfonamide,        A represents an aryl, cycloalkyl, cycloalkenyl group or a        heterocycle, each optionally substituted, and        B represents an aryl group or a 6-membered heterocycle, each        optionally substituted,        as well as their pharmaceutically acceptable salts,        A as defined earlier may be substituted with one or two groups,        either identical or different, selected from:    -   a hydrogen atom, a halogen atom,    -   an alkoxy, alkylthio, haloalkoxy, haloalkylthio, hydroxyl, thio,        cyano, amino, monoalkylamino, or dialkylamino group,    -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or        —NR′SO₂R″ group, wherein R′ and R″ each represent independently        of each other a hydrogen atom, an alkyl, haloalkyl group, and n        has the value 1 or 2,    -   an alkyl or haloalkyl group, the alkyl group being optionally        substituted with a cyano, amino, monoalkylamino, dialkylamino or        acylamino group,    -   an aryl, arylalkyl, —X-aryl, —X-arylalkyl or -Alk-X-aryl group        wherein X represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—,        —SO₂—, —CO— or —CONH—, each substituted on the aryl portion with        one or two substituents, either identical or different, selected        from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono- or di-alkylamide            group,        -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            —NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group and n has the value 1 or 2,    -   a heterocycle, -Alk-heterocycle, —X-heterocycle,        —X-Alk-heterocycle, or -Alk-X-heterocycle group, wherein X        represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—,        —CO—, or —CONH—, each optionally substituted on the heterocycle        portion with one or two substituents either identical or        different, selected from:        -   a hydrogen atom or a halogen atom, an alkyl, haloalkyl,            alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio,            hydroxyl, cyano, acyl, amino, monoalkyl- or dialkylamino,            acid, ester, amide, mono- or di-alkylamide, or        -   a —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group and n has the value 1 or 2,    -   a cycloalkyl, -Alk-cycloalkyl, cycloalkenyl, -Alk-cycloalkenyl,        —X-cycloalkyl, —X-Alk-cycloalkyl, —X-cycloalkenyl,        —X-Alk-cycloalkenyl, -Alk-X-cycloalkyl, -Alk-X-cycloalkenyl        group, wherein X represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—,        —S—, —SO—, —SO₂—, —CO— or —CONH—, each optionally substituted on        the cyclic portion with one or two substituents, either        identical or different, selected from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono- or di-alkylamide,            or oxo or,        -   —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group and n has the value 1 or 2,            B as defined earlier may be an aryl or 6-membered            heterocycle, substituted in the ortho position with a            R₄ group and optionally substituted with a R₅ group,            wherein:    -   R₄ represents:        -   an alkyl, —NHAlk, —NAlkAlk′, —NHcycloalkyl or            —NAlkcycloalkyl group, Alk and Alk′ being identical or            different,        -   a cycloalkyl, cycloalkenyl, N-cycloalkyl or N-cycloalkenyl            group, each optionally substituted with one or two            substituents, either identical or different, selected from a            hydrogen atom, a halogen atom, an alkyl, haloalkyl, alkoxy,            haloalkoxy, thio, alkylthio, haloalkylthio, hydroxyl, cyano,            acyl, amino, monoalkylamino or dialkylamino, acid, ester,            amide, mono- or dialkylamide, oxo or —X-aryl group and            wherein X represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—,            —SO—, SO₂—, —CO— or —CONH—, or an aryl group optionally            substituted with one or two substituents, either identical            or different, a hydrogen atom, a halogen atom, an alkyl,            haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono or dialkylamide or            —X-aryl group, wherein X represents —O—, —NH—, —N(Alk)-,            —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—,    -   R₅ represents:        -   a hydrogen atom or a halogen atom,        -   a hydroxyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, amino, monoalkylamino, dialkylamino, —NHacyl,            cyano, acyl, acid, ester, amide, monoalkylamide or            dialkylamide group,        -   an alkyl or haloalkyl group, the alkyl group may be            substituted with a cyano, hydroxyl, alkoxy, acid or ester            group,        -   a —SO_(n)Alk, —SO_(n)NH₂, —SO_(n)NHAlk or —SO_(n)NAlkAlk′            group, wherein n has the value of 1 or 2 and Alk and Alk′            are either identical or different, or        -   a piperidine, oxopiperidine, morpholine group or else a            piperazine group optionally substituted with an alkyl or            acyl group,

The preferred compounds are the compounds of formula (I) wherein:

G₁ represents a bond or a saturated or unsaturated, linear or branchedhydrocarbon chain comprising 1-4 carbon atoms, optionally substitutedwith one or two alkyl groups, preferably identical,G₂ represents a

group wherein:

-   -   R represents a hydrogen atom, an alkyl, haloalkyl group, or a        prodrug radical such as carbamate, acetyl, dialkylaminomethyl or        —CH₂—O—CO-Alk,    -   G represents a bond or a hydrocarbon chain comprising 1-4 carbon        atoms, linear or branched, saturated or unsaturated, optionally        substituted with one or two alkyl groups, preferably identical,        and    -   W represents an oxygen, sulfur atom or NH,        R₁ and R₂ either identical or different, each represent a group        selected from a hydrogen atom, a halogen atom, a hydroxyl, thio,        alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino,        monoalkylamino, dialkylamino, cycloalkyl, alkyl or haloalkyl        group,        R₃ represents an acid group or a prodrug radical of the acid        function such as ester, or else a bioisoster of the acid        function such as tetrazole, phosphonate, phosphonamide,        sulfonate or sulfonamide,        A represents an aryl or heterocycle group, each being optionally        substituted with one or two groups, either identical or        different, selected from:    -   a hydrogen atom, a halogen atom,    -   an alkoxy, alkylthio, haloalkoxy, haloalkylthio, hydroxyl, thio,        cyano, amino, monoalkylamino or dialkylamino group,    -   a —SO_(n)R′, —COR′—, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or        —NR′SO₂R″ group, wherein R′ and R″ each represent independently        of each other a hydrogen atom, an alkyl, haloalkyl group, and n        has the value 1 or 2,    -   an alkyl or haloalkyl group, the alkyl group being optionally        substituted with a cyano, amino, monoalkylamino, dialkylamino or        acylamino group,    -   an aryl, arylalkyl, —X-aryl group, wherein X represents —O—,        —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—        group, each substituted on the aryl portion with one or two        substituents, either identical or different, selected from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or di-alkylamino, acid, ester, amide, mono- or dialkylamide            group, or        -   a —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            —NR′SO₂R″ groups, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group, and n has the value 1 or 2,    -   a heterocycle, —X-heterocycle group wherein X represents —O—,        —NH—, —N(alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—,        each optionally substituted on the heterocycle portion with one        or two substituents, either identical or different, selected        from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono- or di-alkylamide,            or        -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            —NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group, and n has the value 1 or 2, or    -   a cycloalkyl, cycloalkenyl, —X-cycloalkyl, —X-cycloalkenyl group        where X represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—,        —SO₂—, —CO— or —CONH— group, each optionally substituted on the        cyclic portion with one or two substituents either identical or        different selected from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono- or di-alkylamide,            or oxo, or        -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            —NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group, and n has the value 1 or 2, and            B represents a phenyl or pyridine group:    -   substituted in the ortho position with an N-cycloalkyl group        such as piperidine or with a cyclohexyl, each optionally        substituted with one or two substituents either identical or        different, selected from a hydrogen atom, an alkyl, haloalkyl,        alkoxy, haloalkoxy, —X-aryl group, where X represents —O—, —NH—,        —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—, and/or    -   optionally substituted with a halogen atom or with an alkyl or        haloalkyl group.

The compounds which are still more preferred are the compounds offormula (I) wherein:

G₁ represents a bond or a saturated or unsaturated, linear or branched,hydrocarbon chain comprising 1-4 carbon atoms, optionally substitutedwith one or two alkyl groups, preferably identical,G₂ represents

group wherein:

-   -   R represents a hydrogen atom, an alkyl, haloalkyl group or a        prodrug radical such as a carbamate, acetyl, dialkylaminomethyl,        or —CH₂—O—CO-Alk,    -   G represents a bond or a saturated or unsaturated, linear or        branched hydrocarbon chain comprising 1-4 carbon atoms,        optionally substituted with one or two alkyl groups, preferably        identical, and    -   W represents an oxygen, sulphur atom or NH—,        R₁ and R₂ either identical or different, each represent a group        selected from a hydrogen atom, a halogen atom, a hydroxyl, thio,        alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino,        monoalkylamino, dialkylamino, cycloalkyl, alkyl or haloalkyl        group,        R₃ represents an acid group or a prodrug radical of the acid        function such as an ester, or else a bioisoster of the acid        function such as a tetrazole, phosphonate, phosphonamide,        sulfonate or sulfonamide,        A represents an aryl group optionally substituted with one or        two groups, either identical or different, selected from:    -   a hydrogen atom, a halogen atom,    -   an alkoxy, alkylthio, haloalkoxy, haloalkylthio, hydroxyl, thio,        cyano, amino, monoalkylamino or dialkylamino group,    -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or        —NR′SO₂R″ group, wherein R′ and R″ each represent independently        of each other a hydrogen atom, an alkyl, haloalkyl group, and n        has the value 1 or 2,    -   an alkyl or haloalkyl group, the alkyl group being optionally        substituted with a cyano, amino, monoalkylamino, dialkylamino,        or acylamino group,    -   an aryl, arylalkyl, —X-aryl group, wherein X represents —O—,        —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—,        each substituted on the aryl portion with one or two        substituents, either identical or different, selected from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono- or di-alkylamide            group, or        -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            —NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group, and n has the value 1 or 2,    -   a heterocycle, —X-heterocycle group, wherein X represents —O—,        —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—,        each optionally substituted on the heterocycle portion with one        or two substituents, either identical or different, selected        from:        -   a hydrogen atom or a halogen atom,        -   an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,            haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino            or dialkylamino, acid, ester, amide, mono- or di-alkylamide,            or        -   an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or            —NR′SO₂R″ group, wherein R′ and R″ each represent            independently of each other a hydrogen atom, an alkyl,            haloalkyl group, and n has the value 1 or 2, or    -   a cycloalkyl or —X-cycloalkyl group, wherein X represents —O—,        —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—,        each optionally substituted on the cyclic portion with one or        two substituents, either identical or different, selected from a        hydrogen atom, a halogen atom, an alkyl, haloalkyl, alkoxy,        haloalkoxy, thio, alkylthio, haloalkylthio, hydroxyl, cyano,        acyl, amino, monoalkylamino or dialkylamino, acid, ester, amide,        mono- or di-alkylamide or oxo group, and        B represents a phenyl or pyridine group:    -   substituted in the ortho position with a N-cycloalkyl group such        as piperidine or with a cyclohexyl, each optionally substituted        with one or two substituents, either identical or different,        selected from a hydrogen atom, an alkyl, haloalkyl, alkoxy,        haloalkoxy, —X-aryl, wherein X represents —O—, —NH—, —N(Alk)-,        —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH— group, and/or    -   optionally substituted with a halogen atom or with an alkyl, or        haloalkyl group.

The more preferred compounds are the compounds of formula (I) wherein:

G₁ represents a bond or a saturated or unsaturated, linear or branchedhydrocarbon chain comprising 1-4 carbon atoms, optionally substitutedwith one or two alkyl groups, preferably identical, preferably a bond ora hydrocarbon chain comprising one or two carbon atoms,G₂ represents a group

wherein n is an integer comprised between 1 and 4 and m is an integerhaving the value 1 or 2, preferably n has the value 1 or 2,R₁ represents an alkoxy group, such as methoxy, preferably in the orthoposition relatively to R₃,R₂ represents a hydrogen or halogen atom, such as chlorine or bromine,or an alkyl group, such as methyl, preferably in the meta positionrelatively to R₃,R₃ represents an acid or ester group,A represents an aryl group such as a phenyl, preferably substituted:

in the meta or para position with:

-   -   a halogen atom or an alkyl, haloalkyl, cyano, alkoxy,        haloalkoxy, acylaminoalkyl group or an —XR group, wherein X        represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—,        —CO— or —CONH— group, and R represents an arylalkyl, cycloalkyl        or aryl group, each optionally substituted with one or two        substituents, either identical or different, such as a halogen        atom, an alkoxy, alkyl, haloalkyl, cyano, acyl, amino,        monoalkylamino or dialkylamino, acid, ester, amide, mono- or        di-alkylamide group, or an —SO_(n)R′, —OCOR′, —NR′—COR″ or        —NR′SO₂R″ group, wherein R′ and R″ each represent independently        of each other a hydrogen atom, an alkyl, haloalkyl group, and n        has the value 1 or 2, or    -   a cycloalkyl, aryl, arylalkyl group or heterocycle, preferably        N-cycloalkyl, each optionally substituted with one or two        substituents, either identical or different, such as a halogen        atom, an alkoxy, alkyl, haloalkyl, cyano, acyl, amino,        monoalkylamino or dialkylamino, acid, ester, amide, mono- or        di-alkylamide group, or an —SO_(n)R′, —OCOR′, —NR′COR″, or        —NR′SO₂R′″ group, wherein R′ and R″ each represent independently        of each other a hydrogen atom, an alkyl, haloalkyl group and n        has the value 1 or 2,

and/or in the ortho or meta position with an alkyl group, and

B represents an aryl group, preferably a phenyl,

-   -   substituted in the ortho position with a heterocycle, preferably        a N-cyloalkyl, such as piperidine group, and/or    -   substituted in the ortho′ position with an alkyl group, such as        a methyl.

The more preferred compounds are the compounds of formula (I) wherein:

G₁ represents a bond or a saturated on unsaturated, linear or branchedhydrocarbon chain comprising 1-4 carbon atoms, optionally substitutedwith one or two alkyl groups, preferably identical,preferably a bond or a hydrocarbon chain comprising 1 or 2 carbon atoms,G₂ represents a

group,wherein n is an integer comprised between 1 and 4 and m is an integerhaving the value 1 or 2, preferably n has the value 1 or 2,R₁ represents an alkoxy group, such as methoxy, preferably in the orthoposition relatively to R₃,R₂ represents a hydrogen or halogen atom such as chlorine or bromine, oran alkyl group, such as methyl, preferably in the meta positionrelatively to R₃,R₃ represents an acid or ester group,A represents an aryl group, such as phenyl, preferably substituted:

in the meta or para position with:

-   -   a halogen atom or a cyano, alkoxy, haloalkoxy, acylaminoalkyl or        —XR group, wherein X represents —O—, —S—, —SO—, —SO₂—, or —CO—        and R represents an arylalkyl, cycloalkyl or aryl group, each        optionally substituted with one or two substituents, either        identical or different, such as a halogen atom, an alkoxy or        acyl group, or    -   a cycloalkyl, aryl or arlyalkyl group, each optionally        substituted with one or two substituents, either identical or        different, such as an acyl or alkoxy group, and

and/or in the ortho or meta position with an alkyl group, and

B represents an aryl group, preferably a phenyl,

-   -   substituted in the ortho position with a heterocycle, preferably        a N-cycloalkyl, such as a piperidine group, and/or    -   substituted in the ortho′ position with an alkyl group, such as        a methyl.

The more preferred compounds are the compounds of formula (I) wherein:

G₁ represents a bond or a saturated or unsaturated, linear or branchedhydrocarbon chain comprising 1-4 carbon atoms, optionally substitutedwith one or two alkyl groups, preferably identical,preferably a bond or a hydrocarbon chain comprising 1 or 2 carbon atoms,G₂ represents a

group,wherein n is an integer comprised between 1 and 4, preferably n has thevalue 1,R₁ represents an alkoxy group, such as methoxy, preferably in the orthoposition relatively to R₃,R₂ represents a hydrogen or halogen atom, such as chlorine or bromine,or an alkyl group, such as methyl, preferably in the meta positionrelatively to R₃,R₃ represents an acid or ester group,A represents an aryl group, such as a phenyl, preferably substituted inthe meta or para position with:

-   -   a halogen atom or a alkoxy, haloalkoxy, or —XR group, wherein X        represents —O— and R represents an arylalkyl, cycloalkyl or aryl        group, each optionally substituted with one or two substituents,        either identical or different, such as a halogen atom, an alkoxy        or acyl group, or    -   a cycloalkyl, aryl or arlyalkyl group, each optionally        substituted with one or two substituents, either identical or        different, such as an acyl group, and        B represents an aryl group, preferably a phenyl,    -   substituted in the ortho position with a heterocycle, preferably        a N-cycloalkyl, such as a piperidine group, and/or    -   substituted in the ortho′ position with an alkyl group, such as        a methyl.

Still more preferred compounds are grouped in Table I:

TABLE I  1 5-brom-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2(piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]- benzoic acidhydrochloride  2 5-bromo-2-methoxy-4-[N-(2-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazinocarbonyl- methyl]-benzoic acidhydrochloride  3 5-bromo-2-methoxy-4-[N-(3-methoxy-benzyl)-N-(2-piperidin1-yl-phenyl)-hydrazinocarbonylmethyl]- benzoic acidhydrochloride  4 4-[N-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)hydrazinocarbonylmethyl]-5-bromo-2-methoxy- benzoic acidhydrochloride  5 5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2- methoxy-benzoic acidhydrochloride  6 5-bromo-2-methoxy-4-{N-[2-(4-methoxy-phenyl)-ethyl]-N-2-piperidin-1-yl-phenyl)-hydrazino- carbonylmethyl}-benzoic acidhydrochloride  7 5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino- carbonylmethyl]-benzoic acidhydrochloride  7a Methyl 5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino- carbonylmethyl]-benzoate 8 5-bromo-2-methoxy-4-[N-(4-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]- benzoic acidhydrochloride  9 5-bromo-4-[N-(4-cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy- benzoic acidhydrochloride 10 5-bromo-2-methoxy-4-[N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazino- carbonylmethyl]-benzoicacid hydrochloride 115-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]- benzoic acidhydrochloride 12 5-bromo-4-[N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2- methoxy-benzoic acidhydrochloride 13 5-bromo-2-methoxy-4-[N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]- benzoic acidhydrochloride 14 5-bromo-4-{N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2- methoxy-benzoic acidhydrochloride 15 4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2- methoxy-benzoic acidhydrochloride 16 5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl}-2-methoxy-benzoic acid hydrochloride  16a Methyl5-Bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl}-2-methoxy-benzoate 174-[N-(4-benzyl-phenyl)-N-(2-piperidin-1-yl-phenyl)hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride 184-[N-(4-bromo-phenyl)-N-(2-piperidin-1-yl-phenyl)hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoic acid hydrochloride19 4-[N-(3′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy- benzoic acidhydrochloride 20 4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy- benzoic acidhydrochloride 21 5-bromo-2-methoxy-4-[N-(3-phenoxy)-phenyl]-N-(2piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]- benzoic acidhydrochloride 22 5-bromo-2-methoxy-4-[N-(4-phenylsulfanyl)-phenyl]-N-(2piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]- benzoic acidhydrochloride 23 4-[N-(4-benzenesulfonyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy- benzoic acidhydrochloride 24 4-[N-(4-benzenesulfinyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy- benzoic acidhydrochloride 25 2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]- vinyl}-benzoic acidhydrochloride 26 5-bromo-2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino- carbonyl]-vinyl}-benzoicacid hydrochloride 274-[N-(4-benzyl-phenyl]-N-(2-methyl-6-piperidin-l-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy- benzoic acidhydrochloride 28 5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-l-yl-phenyl)-hydrazino- carbonyl-methyl]-benzoicacid hydrochloride 30 4-[N-(acetylamino-methyl)-phenyl]-N-(2-methyl-6-piperidin-l-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride 315-bromo-4-[N-(4-cyano-phenyl)-N-(2-methyl-6-piperidin-l-yl-phenyl)-hydrazinocarbonylmethyl]-2- methoxy-benzoic acidhydrochloride 32 4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-l-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride 335-bromo-2-methoxy-4-[N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoic acid hydrochloride

The object of the present invention is also the pharmaceuticalcompositions comprising at least one compound of formula (I), associatedwith a pharmaceutically acceptable excipient.

The pharmaceutical compositions according to the invention may becompositions which may be administered into the organism via anyadministration route. In an non-exhaustive way, the administration routeof the pharmaceutical compositions according to the invention may betopical, enteral or parenteral, preferably a buccal, conjunctive,cutaneous, endotracheal, intradermal, intra-epidermal, intramuscular,intravascular, laryngeal, nasal, ophthalmic, oral, rectal, respiratory,sub-cutaneous, transcutaneous or vaginal administration. It is generallyadvantageous to formulate such pharmaceutical compositions as a singledose. Each dose then comprises a predetermined amount of the activeingredient, associated with the vehicle, suitable excipients and/oradjuvants, calculated in order to obtain a given therapeutic effect. Asan example of a single dose which may be administered via an oral route,mention may be made of tablets, gelatin capsules, granules, powders andoral solutions or suspensions. As an example of single dose which may beadministered via a topical route (notably for local treatment ofexternal genital and perianal warts), mention may be made of ovules,gels, creams, lotions, solutions and patches.

The suitable formulations for the selected dosage forms are known anddescribed for example in Remington, The Science and Practice ofPharmacy, 19^(th) edition, 1995, Mack Publishing Company and maytherefore be easily prepared by one skilled in the art.

It is known that dosage varies from one individual to the other,depending on the nature and the intensity of the disease, the selectedadministration route, the weight, the age, and the sex of the patient;accordingly the effective dosages should be determined according tothese parameters by the specialist in this matter. As an indication, theeffective dosages may range between 1 and 500 mg daily.

The object of the present invention is also the use of the compounds offormula (I) for treating or preventing an infection by the papillomavirus, preferably in humans.

The object of the present invention is also the use of the compounds offormula (I) for inhibiting the replication of the papilloma virus byinhibiting the formation of the E1/E2 protein complex.

The object of the present invention is further the use of the compoundsof formula (I) for preparing a drug intended for treating or preventinginfection by the papilloma virus, preferably in humans.

The object of the present invention is in particular the use ofcompounds of formula (I) for preparing a drug intended for treating orpreventing infection by a low risk papilloma virus, such as HPV6, HPV7,HPV11, HPV13, HPV32, HPV34, HPV40, HPV42, HPV43, HPV44, HPV53, HPV54,HPV55, HPV57, HPV58, HPV74, HPV91.

The object of the present invention is in particular the use ofcompounds of formula (I) for preparing a drug intended for treating orpreventing an infection by HPV6 and/or HPV11.

Thus, the object of the present invention is also the use of compoundsof formula (I) for preparing a drug intended for treating or preventinglesions and diseases associated with infections by the papilloma virus.

The object of the present invention is in particular the use ofcompounds of formula (I) for preparing a drug intended for treating andpreventing anogenital warts, such as acuminated condylomas and planecondylomas, laryngeal, conjunctive or buccal papillomas and otherepithelial lesions such as respiratory recurrent papillomatoses andintra-epithelial neoplasias of low grade and of high grade, bowenoidpapuloses, warts (verruca vulgaris, verruca plantaris, myrmecia wart,surface warts, verruca plana . . . ), epidermodysplasia verruciformis,carcinomas, in particular anogenital carcinomas, and all the lesionswhich are associated with the papilloma virus.

The object of the present invention is in particular the use ofcompounds of formula (I) for preparing a drug intended for treating orpreventing anogenital warts, such as acuminated condylomas and planecondylomas, laryngeal, conjunctive or buccal papillomas and otherepithelial lesions, such as respiratory recurrent papillomatoses and lowgrade intra-epithelial neoplasias and all the lesions which areassociated with the papilloma virus.

The compounds, objects of the present invention, may be preparedaccording to the various synthesis routes described hereafter.

The compounds wherein

G₂ represents the

radical as defined earlier may be prepared in the following way.

When W represents an oxygen atom, ester precursors of compounds offormula (I) are obtained from intermediates of the following formulae(II) and (III):

In formula (II), A, B and G₁, are as defined earlier. In formula (III),R₁, R₂ and G, are as defined earlier and P represents a group protectingan acid function, such as a linear or branched (C₁-C₄)alkyl.

In this case, peptide coupling is carried out between the compounds (II)and (III) for example in the presence of EDCI in a basic and apolarmedium in order to lead to the compound of formula (IV):

The compound (IV) may also be obtained in the following way. Thecompound (III) is transformed into the corresponding acid chloride offormula (V) by the action of thionyl chloride for example,

wherein R₁, R₂, G and P are as defined earlier and which are reacted onthe compound (II).

Next, deprotection of the —CO₂P group of the compound of formula (IV) isperformed by hydrolysis, in order to obtain the compound of formula (I)

wherein W represents an oxygen atom and R₃ is as defined earlier.

If necessary, the compound of formula (I) obtained upon completion ofthe deprotection step or else the compound of formula (IV) is reactedwith Lawesson's reagent, so that the compound of formula (VI) may beobtained:

which, after hydrolysis, corresponds to the case when W represents asulfur atom in formula (I). Lawesson's reagent may for example be[2,4-bis(4-methoxyphenyl)1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson et al. Bull. Soc. Chim Belg. 1978, 87, 229).

In the case when G₁ represents a bond, the compounds of formula (II) maybe obtained from compounds of formula (VII):

wherein B is as defined earlier.

The compounds of formula (VII) are submitted to an aromatic nucleophilicsubstitution, in a basic and polar medium in the presence of compounds(VIII) of formula.

wherein A is as defined earlier and G₁ represents a bond, and compoundsof formula (IX) are obtained:

wherein A and B are as defined earlier.

In the case when G₁ represents a hydrocarbon chain as defined in formula(I), the compound of formula (X) is reacted:

wherein A and G₁ are as defined earlier and X represents a halogen atom,under basic and polar conditions, with a compound of formula (XI):

wherein B is as defined earlier, and compounds of formula (XII) areobtained:

wherein A, B and G, are as defined earlier;

The compounds of formulae (IX) and (XII) are put into the presence ofsodium nitrite in an acid medium and then reduced by a hydride, forexample lithium aluminium hydride (J. Org. Chem. 1953, 18, 971, J. Org.Chem. 1954, 19, 1157, and J. Am. Chem. Soc. 1952, 74, 3192) in order toobtain the compounds of formula (II) as defined earlier.

In the case when R₂ represents a hydrogen or bromine atom, the compoundsof formula (III) may be obtained according to methods of the literature(J. Med. Chem. 1998, 41, 5219 or WO 0135900).

In the case when R₂ represents a chlorine atom, the compounds of formula(III) may be obtained by reacting sulfuryl chloride in an acid mediumwith a precursor of formula (XIII):

wherein R₁, G and P are as defined earlier.

The compounds of formulae (VII), (VIII), (X) and (XI) are eithercommercial compounds or compounds obtained according to known methods oforganic synthesis easily accessible and easily understood by one skilledin the art.

In the preferred case when B is a phenyl substituted with a piperidine,compounds of formula (I) may be prepared according to the followingsynthesis route.

In the case when G, represents a bond, compounds of formula (II) may beobtained from compounds of formula (XIV):

wherein R₅ is as defined earlier.

The compounds of formula (XIV) are submitted to an aromatic nuclophilicsubstitution in a basic and polar medium in the presence of compounds(VIII), and compounds of formula (XV) are obtained:

wherein A and R₅ are as defined earlier.

The compounds of formula (XV) are reduced by tin chloride in a polarmedium (Tet. Lett. 1984, 25 (8), 839) and then reacted with adibromoalkane, for example dibromopentane in a basic and apolar medium(Bioorg. Med. Chem. Lett. 1996, 6 (5), 563) leading to the compounds offormula (XVI):

wherein A and R₅ are as defined earlier.

In the case when G₁ represents a hydrocarbon chain, as defined informula (I), the compound of formula (X) is reacted under basic andpolar conditions, with a compound of formula (XVII):

wherein R₅ is as defined earlier, and the compounds of formula (XVIII)are obtained:

wherein A, G₁ and R₅ are as defined earlier.

The compounds of formula (XVI) and (XVIII) are put into the presence ofsodium nitride in an acid medium and then reduced by a hydride, forexample lithium aluminium hydride in order to obtain the compounds offormula (II) as defined earlier.

In the particular case when A represents a substituted phenyl and G₁ isa bond, the compounds of formula (I) may be prepared according to thefollowing synthesis route.

The compound of formula (XIX) is reacted:

wherein B, G, R₁, R₂ and P are as defined earlier and Y represents ahalogen such as bromine or iodine or a triflate group, under basicconditions for coupling to palladium, with a compound of formula (XX):

wherein C represents an aryl or a heterocycle substituted in variousways, leading to the compound (XXI) of formula:

wherein B, C, G, R₁, R₂ and P are as defined earlier.

Next, the compound (XXI) is reacted under basic saponificationconditions in order to lead to the compound of general formula (I).

The compounds whereinG₂ represents the

radical as defined earlier may be prepared in the following way.

The compounds of formula (IX) or (XII) as described earlier are reactedwith a compound of formula (XXII):

wherein R₁, R₂, G and P are as defined earlier,either directly in the presence of triphosgene for example or by priortransformation of one of the precursors into carbamoyl chloride. And afinal hydrolysis is then carried out.

The compound (XXII) may be obtained from the compound (XXIII) offormula:

wherein R₁, R₂, G and P are as defined earlier, by reacting the compound(XXIII) in the presence of hexamethylenetetramine (HMTA) in an apolarsolvent followed by acid treatment.

The compounds wherein

G₂ represents the

radical as defined earlier may also be prepared in the following way.

When W represents an oxygen atom, the ester precursors of the compoundsof formula (I) are obtained from the following intermediates of formulae(XXIV) and (V):

In formula (XXIV), A, B and G₁, are as defined earlier.

In formula (V), R₁, R₂ and G are as defined earlier and P represents agroup protecting an acid function, such as a linear or benched C₁-C₄alkyl.

In this case, the compound (V) is reacted on the compound (XXIV) in anacid medium in order to lead to the compound of formula (IV):

Next, deprotection of the —CO₂P group of the compound of formula (IV) isperformed by hydrolysis, in order to obtain the compound of formula (I):

wherein W represents an oxygen atom and R₃ is as defined earlier.

In the preferred case, when B is a phenyl substituted with a piperidineand when G₁ represents a bond, the compounds of formula (XXIV) may beobtained from compounds of formula (XIV):

wherein R₅ is as defined earlier.

The compounds of formula (XIV) are submitted to an aromatic nucleophilicsubstitution in a polar medium in the presence of commercialBoc-hydrazine, and the compounds of formula (XXV) are obtained:

wherein R₅ is as defined earlier.

The compound of formula (XXV) is put into the presence of manganeseoxide (Org. Letters, 2006, 8, 1, 43) and then submitted to anN-arylation reaction leading to the compounds of formula (XXVI):

wherein A and R₅ are as defined earlier.

The compounds of formula (XXVI) are reduced by catalytic hydrogenationand then reacted with a dibromoalkane or an acid chloride, for example5-bromovaleryl chloride, in a basic and apolar medium, and then cyclizedin a basic and polar medium such as by sodium hydride indimethylformamide and finally reduced by borane, in order to lead to thecompound of formula (XXVII):

wherein A and R₅ are as defined earlier.

The object of the present invention is also the synthesis intermediatescorresponding to the compounds (II) grouped in the Table (II).

TABLE II a N-(4-methoxy-phenyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine bN-(2-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy- phenyl)-hydrazine cN-(3-methoxy-benzyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine dN-(4-benzyloxy-phenyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine eN-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1- yl-phenyl)-hydrazine fN-[2-(4-methoxy-phenyl)-ethyl]-N-(2-piperidin-1-yl- phenyl)-hydrazine gN-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl- phenyl)-hydrazine hN-(4-methoxy-benzyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine iN-(4-cyclohexyl-phenyl)-N-(2-piperidin-l-yl- phenyl)-hydrazine jN-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazine kN-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-l-yl- phenyl)-hydrazine lN-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl- phenyl)-hydrazine mN-(4-phenoxy-phenyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine nN-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1- yl-phenyl)-hydrazine oN-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine pN-(4-benzyl-phenyl]-N-(2-piperidin-l-yl-phenyl)- hydrazine qN-(4-bromo-phenyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine rN-(3-phenoxy-phenyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine sN-(4-phenylsulfanyl-phenyl)-N-(2-piperidin-1-yl- phenyl)-hydrazine tN-(4-benzyl-phenyl)-N-(2-methyl-6-piperidin-1-yl- phenyl)-hydrazine uN-(4′-methoxy-bipheny1-4-yl)-N-(2-methy1-6-piperidin-l-yl-phenyl)-hydrazine vN-(4-benzoyl-phenyl)-N-(2-piperidin-l-yl-phenyl)- hydrazine wN-[4′-(2-methyl-[1,3]dithian-2-yl)-biphenyl-4-yl]-N-(2-methy1-6-piperidin-1-yl-phenyl)-hydrazine xN-(4′-methoxy-2-methyl-bipheny1-4-yl)-N-(2-methy1-6-piperidin-l-yl-phenyl)hydrazine

The following examples illustrate the invention but do not limit it byany means.

The starting products used are commercial products or products preparedaccording to known operating procedures from commercial compounds orknown to one skilled in the art. The different preparations lead tosynthesis intermediates useful for preparing the compounds of theinvention.

The structures of the compounds described in the examples and in thepreparations were determined according to the usual spectrophotometrictechniques (nuclear magnetic resonance (NMR), mass spectrometry (MS),including electrospray (ES), melting point (MP) . . . ) and purity wasdetermined by high performance liquid chromatography (HPLC) andconfirmed by elementary analysis.

Abbreviations used in the operating procedures:

-   -   AIBN: 2,2′-azobis(2-methylpropionitrile)    -   TLC: thin layer chromatography    -   EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   DMAP: 4-dimethylaminopyridine    -   DMSO: dimethylsulfoxide    -   DIPEA: N,N-diisopropylethylamine    -   HOBt: 1-hydroxybenzotriazole    -   TFA: trifluoroacetic acid

Preparation 1: methyl 4-carboxymethyl-2-methoxy-benzoate

Methyl 4-carboxymethyl-2-methoxy-benzoate may be prepared according tothe method described in J. Med. Chem. 1998, 41, 5219 or patent WO0135900.

Preparation 2: methyl 5-bromo-4-carboxymethyl-2-methoxy-benzoate

Methyl 5-bromo-4-carboxylmethyl-2-methoxy-benzoate is obtained from thepreparation 1 according to the procedure described in WO 0135900.

Preparation 3: methyl 5-chloro-4-carboxymethyl-2-methoxy-benzoate

To 300 mg of methyl 4-carboxymethyl-2-methoxy-benzoate from preparation1 placed in 6 mL of acetic acid, are added 110 μL of sulfuryl chloride(1 equivalent). The whole is refluxed for 6 hours. After evaporation ofthe solvent, the reaction crude product is purified on silica gel(petroleum ether/ethyl acetate: 80/20 then 60/40) leading to 165 mg ofthe desired compound.

Yield: 47%

HPLC: 96%

MS: MH⁺ 259/261

Preparation 4: methyl 4-((E)-2-carboxy-vinyl)-2-methoxy-benzoate Stage1: methyl 4-bromomethyl-2-methoxy-benzoate

To 5.38 g of methyl 2-methoxy-4-methyl benzoate in 20 mL of carbontetrachloride, are added 5.3 g of N-bromosuccinimide (1 equivalent) and490 mg of AIBN (0.1 equivalent) away from direct light. The whole isrefluxed by heating overnight. The reaction medium is evaporated underreduced pressure and then purified on silica gel (petroleum ether/ethylacetate: 90/10) leading to 3.73 g of the desired product.

Yield: 48%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.76 (d, 1H), 6.99 (m, 2H), 4.46 (s,2H), 3.92 (s, 3H), 3.88 (s, 3H)

HPLC: 96%

MS: MH⁺ 259/261

Stage 2: methyl 4-Hydroxymethyl-2-methoxy-benzoate

To 1.5 g of the product obtained in the previous stage in 25 mL ofdioxane is added a suspension of 2.55 g (4.4 equivalents) of calciumcarbonate in 25 mL of water. The whole is heated for 6 hours at 100° C.After evaporation of the reaction medium, the crude product is taken upin dichloromethane, acidified with a 1 N hydrochloric acid solution. Thereaction medium is extracted several times with dichloromethane, thecollected organic phases are then dried on magnesium sulfate, filteredand evaporated under reduced pressure, leading to 1.10 g of the desiredproduct.

Yield: 96%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.78 (d, 1H), 7.01 (m, 1H), 6.93 (d,1H), 4.73 (s, 2H), 3.91 (s, 3H), 3.88 (s, 3H)

Stage 3: methyl 4-formyl-2-methoxy-benzoate

To 1.10 g of the product obtained in the previous stage in 20 mL ofdioxane are added 4.87 g of activated manganese oxide (10 equivalents).The whole is stirred at room temperature for 24 hours, and then filteredon celite. The filtrate is evaporated under reduced pressure and theobtained residue is purified by chromatography on silica gel (petroleumether/ethyl acetate: 90/10 and then 80/20) leading to 540 mg of thedesired product.

Yield: 50%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 10.02 (s, 1H), 7.89 (d, 1H), 7.48 (m,2H), 3.97 (s, 3H), 3.92 (s, 3H)

Stage 4: methyl 4-((E)-2-tert-butoxycarbonyl-vinyl)-2-methoxy-benzoate

To 720 μL of tert-butyl diethylphosphonoacetate (1.1 equivalents) in 3mL of tetrahydrofurane cooled to 0° C. under an inert atmosphere areadded 307 mg of sodium tert-butanolate (1.15 equivalents). The whole isstirred for 30 minutes at 0° C. and then for 1 hour at room temperature.A solution cooled to 0-4° C. of 540 mg of aldehyde obtained in stage 3in 1 ml of tetrahydrofurane is added dropwise to the previous mixturealso cooled to 0° C. Stirring is maintained at this temperature for 30minutes before letting the temperature rise back to room temperature for2 hours. The medium is hydrolyzed with a saturated solution of ammoniumchloride and extracted with ethyl acetate several times. The collectedorganic phases are washed with water, and then dried on magnesiumsulfate, filtered and evaporated under reduced pressure. The reactioncrude product is purified by chromatography on silica gel (petroleumether/ethyl acetate: 95/5) leading to 500 mg of the expected product.

Yield: 61%

¹H NMR (DMSO, 300 MHz) δ (ppm): 7.48-7.66 (bulk aromatic, 3H), 6.70 (d,1H), 3.87 (s, 3H), 3.79 (s, 3H), 1.49 (s, 9H)

HPLC: 93%

MS: MH⁺ 293

Stage 5: methyl 4-((E)-2-carboxy-vinyl)-2-methoxy-benzoate

To 100 mg of diester obtained in the previous stage in 1.6 mL ofdichloromethane are added 0.8 mL of trifluoroacetic acid. The whole isstirred for one hour at room temperature and then evaporated underreduced pressure with a toluene and dichloromethane mixture asco-solvents.

Yield: 99%

¹H NMR (DMSO, 300 MHz) δ (ppm): 7.57-7.67 (m, 2H), 7.47 (s, 1H), 7.32(d, 1H), 6.67 (d, 1H), 3.87 (s, 3H), 3.79 (s, 3H)

HPLC: 90%

Preparation 5: methyl 5-bromo-4-((E)-2-carboxy-vinyl)-2-methoxy-benzoateStage 1: methyl 5-bromo-4-bromomethyl-2-methoxy-benzoate

To 2.5 g of methyl 2-methoxy-4-methyl benzoate in 15 mL of acetic acidare added dropwise 550 μL of bromine (1.1 equivalents) at roomtemperature. The whole is stirred for one night, until completedisappearance of the starting product (tracked by TLC). The reactionmedium, hydrolyzed by a 1 N soda solution, is extracted with ethylacetate. The organic phases are dried on magnesium sulfate and thenconcentrated under reduced pressure, leading to 2.72 g of a pale yellowoil which crystallizes.

Yield: 83%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.98 (s, 1H), 7.06 (s, 1H), 4.55 (s,2H), 3.92 (s, 3H), 3.89 (s, 3H)

HPLC: 85%

MS: MH⁺ 336/338/340

Stage 2: methyl 5-bromo-4-hydroxymethyl-2-methoxy-benzoate

The product (880 mg) is obtained according to the method of stage 2 ofpreparation 4 from 1.3 g of product from the previous stage in thepresence of 1.7 g of calcium carbonate.

Yield: 83%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.96 (s, 1H), 7.20 (s, 1H), 4.75 (s,2H), 3.92 (s, 3H), 3.88 (s, 3H)

HPLC: 96%

MS: MH⁺ 275/277

Stage 3: methyl 5-bromo-4-formyl-2-methoxy-benzoate

The product (725 mg) is obtained according to the method of stage 3 ofpreparation 4, by using 875 mg of the previous alcohol in the presenceof 2.8 g of activated manganese oxide.

Yield: 83%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 10.33 (s, 1H), 8.01 (s, 1H), 7.49 (s,1H), 3.95 (s, 3H), 3.92 (s, 3H)

HPLC: 96%

MS: MH⁺ 273/275

Stage 4: methyl5-bromo-4-((E)-2-tert-butoxycarbonyl-vinyl)-2-methoxy-benzoate

The product (860 mg) is obtained according to the method of stage 4 ofpreparation 4, by using 725 mg of the previous aldehyde in the presenceof 688 μL of tert-butyl diethylphosphonoacetate and 293 mg of sodiumtert-butanolate.

Estimated yield: 87%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.00 (s, 1H), 7.89 (d, 1H), 7.13 (s,1H), 6.34 (d, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 1.55 (s, 9H)

HPLC: 63%

MS: MH⁺ 371/373

Stage 5: methyl 5-bromo-4-((E)-2-carboxy-vinyl)-2-methoxy-benzoate

The product (489 mg) is obtained according to the method of stage 5 ofpreparation 4, by using 860 mg of the previous cinnamic ester in thepresence of 5 mL of trifluoroacetic acid.

Yield: 67%

¹H NMR (DMSO, 300 MHz) δ (ppm): 7.88 (s, 1H), 7.75 (d, 1H), 7.57 (s,1H), 6.83 (d, 1H), 3.90 (s, 3H), 3.80 (s, 3H)

HPLC: 89%

MS: MH⁺ 315/317

EXAMPLE 15-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (1) Stage 1:(4-methoxy-phenyl)-(2-nitro-phenyl)-amine

To 3.7 mL of 2-fluoro-nitrobenzene are added 8.73 g of 4-methoxyaniline(2 equivalents). The whole is heated to 110° C. overnight. The medium istaken up in ethyl acetate, successively washed with water, a saturatedsolution of sodium bicarbonate and then with a saturated solution ofsodium chloride. The organic phase is dried on magnesium sulfate,filtered and then concentrated under reduced pressure. With silica gelchromatography of the residue (petroleum ether/ethyl acetate: 90/10)8.63 g of the desired product are isolated.

Yield: 99%

¹H NMR (DMSO, 300 MHz) δ (ppm): 9.35 (s, 1H), 8.10 (d, 1H), 7.45 (t,1H), 7.25 (d, 2H), 6.98 (m, 3H), 6.79 (t, 1H), 3.78 (s, 3H)

HPLC: 100%

Stage 2: N-(4-methoxy-phenyl)-benzene-1,2-diamine

To a solution of 4 g of the product obtained in the previous stage in 80mL of ethanol are added 18.5 g of tin chloride hydrate (5 equivalents).The whole is refluxed for 5 hrs and then stirred at room temperatureovernight. The medium is hydrolyzed under cold conditions, adjusted to apH of 8 with a saturated solution of sodium bicarbonate and extractedwith ethyl acetate several times. The collected organic phases are driedon magnesium sulfate, filtered and evaporated in vacuo. The obtainedresidue is purified by silica gel chromatography (toluene and thentoluene/ethyl acetate: 95/5) leading to 2.9 g of the expected product.

Yield: 82%

¹H NMR (DMSO, 300 MHz) δ (ppm): 6.89 (d, 1H), 6.75 (m, 7H), 6.50 (t,1H), 4.67 (s, 2H), 3.67 (s, 3H)

HPLC: 100%

Stage 3: (4-methoxy-phenyl)-(2-piperidin-1-yl-phenyl)-amine

To a solution de 2.5 g of aniline obtained earlier in 15 mL of toluene,are successively added 2.47 g of de sodium carbonate (2 equivalents) and1.6 mL of dibromopentane (1 equivalent). The whole is refluxed for 24hrs. After returning to room temperature, the sodium carbonate isremoved by filtration and rinsed with dichloromethane. The filtrate isevaporated under reduced pressure. The obtained residue is purified bysilica gel chromatography (petroleum ether, petroleum ether/ethylacetate: 98/2) leading to 1.72 g of the desired product.

Yield: 52%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.10 (m, 4H), 6.92 (m, 3H), 6.78 (m,1H), 6.52 (s, 1H), 3.81 (s, 3H), 2.86 (m, 4H), 1.71 (m, 4H), 1.60 (m,2H)

HPLC: 100%

Stage 4: N-(4-methoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (a)

806 mg of the product obtained in the previous stage are solubilized in10 mL of acetic acid. To this solution cooled between 5 and 15° C. isadded dropwise a solution of 1.14 g of sodium nitride in 3 mL of water(5.8 equivalents). After 10 minutes of stirring, ice is added into thereaction medium, the formed precipitate is filtered, washed with waterand then dried in vacuo.

A brown powder corresponding to the nitroso intermediate is obtained(followed by TLC and NMR). This non-purified intermediate, taken up in 8mL of diethyl ether, is directly cooled to 10° C. To this solution isadded a suspension of 119 mg of lithium aluminium hydride (1.1equivalents) in 2 mL of diethyl ether. The whole is stirred for 1 hruntil complete disappearance of the starting product (tracked by TLC).The reaction medium is poured onto a 1 N soda solution and extractedseveral times with diethyl ether. The organic phase is dried, filteredand evaporated under reduced pressure leading to a residue which ispurified by chromatography (petroleum ether/ethyl acetate: 95/5). 382 mgof product corresponding to hydrazine are obtained as pink oil.

Yield: 45%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.08 (m, 5H), 6.95 (m, 1H), 6.81 (m,2H), 3.78 (s, 3H), 3.04 (m, 4H), 1.73 (m, 4H), 1.57 (m, 2H)

Stage 5: methyl5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoate

To a solution of 367 mg of the previous compound in 10 mL ofdichloromethane are added 412 mg of the acid of the preparation 2 (1.1equivalents), 260 mg of EDCI (1.1 equivalents) and 45 mg of DMAP (0.3equivalent). The reaction medium is stirred at room temperature, and ifnecessary heated, until complete disappearance of the starting hydrazine(time >15 hrs) and then hydrolyzed and extracted with dichloromethaneseveral times. The organic phases are washed with a 1 N soda solutionand then with a saturated solution of sodium chloride, dried onmagnesium sulfate, filtered and evaporated under reduced pressure. Theobtained residue is purified by silica gel chromatography (petroleumether/ethyl acetate: 72/25 and then 70/30) leading to 546 mg of theexpected product.

Yield: 76%

¹H NMR (DMSO, 300 MHz) δ (ppm): 10.65 (s, 1H), 7.81 (s, 1H), 7.30 (m,2H), 6.99 (m, 4H), 6.72 (m, 4H), 3.79 (2s broad, 8H), 3.69 (s, 3H), 2.50(s broad, 4H), 1.12 (m, 6H) HPLC: 96%

Stage 6:5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl]-benzoicacid hydrochloride (1)

To a solution of 100 mg of the product obtained in stage 5, in 2 mL ofdioxane are added 343 μL of a 1 N soda solution (2 equivalents). Thereaction medium is stirred at room temperature for 4 hrs and thenconcentrated under reduced pressure. The obtained solid is taken up in aminimum of water and acidified with a 1 N hydrochloric acid solution upto a pH of 1. In the present case, extraction with dichloromethaneallows the reaction crude product to be isolated. After evaporation, theresidue is taken up in ether. A precipitate is formed which is filteredand washed leading to 52 mg of the expected product as a hydrochloride.

Yield: 50%

MP: 109° C. (decomposition)

Elementary analysis calculated for C₂₈H₃₀BrN₃O₅.1HCl.1.5H₂O: C, 53.22;H, 5.42; N, 6.65. Found: C, 52.84; H, 5.08; N, 6.24.

HPLC: 97%

MS: MH⁺ 568/570

EXAMPLE 25-bromo-2-methoxy-4[N-(2-piperidin-1-yl-phenyl)-N(4-trifluoromethoxy-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride(2) Stage 1:(2-Nitro-phenyl)-(4-trifluoromethoxy-phenyl)-amine

To 374 μL of 2-fluoro-nitrobenzene in 2 mL of DMSO are added 962 μL of4-trifluoromethoxyaniline (2 equivalents) and 636 mg of potassiumtert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 3hrs. Once the reaction is completed, the medium taken up in a minimum ofdichloromethane is hydrolyzed and then extracted. The organic phase issuccessively washed with water and then with a saturated solution ofsodium chloride, dried on magnesium sulfate, filtered and concentratedunder reduced pressure. A silica gel chromatography of the residue(cyclohexane and then cyclohexane/ethyl acetate: 99/1) allows 575 mg ofthe desired product to be isolated.

Yield: 54%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.43 (s, 1H), 8.22 (d, 1H), 7.43 (t,1H), 7.25-7.38 (m, 4H), 7.19 (d, 1H) 6.83 (t, 3H)

HPLC: 97%

MS: MH⁺ 299

Stage 2: N-(4-Trifluoromethoxy-phenyl)-benzene-1,2-diamine

The product (600 mg) is obtained according to the method of stage 2 ofExample 1, by using 570 mg of the previous derivative as a startingproduct and 2.16 g of tin chloride hydrate in 10 mL of ethanol.

Yield: quantitative ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.01-7.12 (m, 4H),6.73-6.86 (m, 2H), 6.70 (m, 2H), 5.30 (s broad, 1H)

HPLC: 96%

MS: MH⁺ 269

Stage 3: (2-Piperidin-1-yl-phenyl)-(4-trifluoromethoxy-phenyl)-amine

The product (350 mg) is obtained according to the method of stage 3 ofExample 1, by using 513 mg of the previous aniline as substrate and 261μL of dibromopentane in the presence of 405 mg of sodium carbonate in 5mL of toluene.

Yield: 54%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.28 (m, 2H), 7.13 (s, 3H), 7.09 (d,1H), 7.01 (t, 1H), 6.88 (t, 1H), 6.70 (s, 1H), 2.83 (m, 4H), 1.71 (m,4H), 1.59 (m, 2H)

Stage 4:N-(2-Piperidin-1-yl-phenyl)-N-(4-trifluoro-methoxy-phenyl)-hydrazine (b)

The product (180 mg) is obtained according to the method of stage 4 ofExample 1 by using 345 mg of the previous derivative as a startingproduct and 410 mg of sodium nitrite in 4 mL of acetic acid leading tothe nitroso intermediate which is reduced by 28 mg of lithium aluminiumhydride in 4 mL of diethyl ether.

Yield: 50%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.04-7.22 (bulk aromatic, 8H), 3.09 (m,4H), 1.83 (m, 4H), 1.59 (m, 2H)

MS: MH⁺ 352

Stage 5: methyl5-bromo-2-methoxy-4[N-(2-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazino-carbonylmethyl]-benzoate

The product (250 mg) is obtained according to the method of stage 5 ofExample 1, by using 176 mg of the preceding hydrazine as substrate and167 mg of the acid of the preparation 2 as a co-substrate in thepresence of 106 mg of EDCI and 18 mg of DMAP.

Yield: 78%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.32 and 9.35 (2s in proportions 70/30,1H), 7.93 and 7.99 (2s in proportions 30/70, 1H), 6.74-7.50 (m, 9H),3.70-4.07 (3s, 8H), 2.67 (m, 4H), 1.43-1.56 (m, 6H)

HPLC: 98%

MS: MH⁺ 636/638

Stage 6:5-bromo-2-methoxy-4[N-(2-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazino-carbonylmethyl]-benzoicacid hydrochloride (2)

To a solution of 100 mg of the product obtained in stage 5 in 2 mL ofdioxane is added 1.6 mL of a 1 N soda solution (10 equivalents). Thereaction medium is stirred at room temperature for 4 hrs and thenconcentrated under reduced pressure. The obtained solid is taken up in aminimum of water and acidified with a 1 N hydrochloric acid solution upto a pH of 1. A precipitate is formed, which is filtered, taken up inether and washed leading to 52 mg of the expected product as ahydrochloride.

Yield: 69%

MP: 157° C. (decomposition)

Elementary analysis calculated for C₂₈H₂₇BrF₃N₃O₅.1HCl.1H₂O: C, 49.68;H, 4.47; N, 6.21. Found: C, 50.01; H, 4.62; N, 5.91.

HPLC: 98%

MS: MH⁺ 622/624

EXAMPLE 35-bromo-2-methoxy-4-[N-(3-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (3) Stage 1:(3-methoxy-benzyl)-(2-piperidin-1-yl-phenyl)-amine

To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 795 μL of3-methoxybenzyl bromide (1 equivalent) and 1.57 g of potassium carbonate(2 equivalents). The whole is heated to 100° C. for 2-3 hrs, untildisappearance of the starting aniline. The medium is poured onto ice andthen extracted with ethyl acetate. The organic phase washed with wateris dried on magnesium sulfate, filtered and evaporated under reducedpressure. By silica gel chromatography of the residue (cyclohexane/ethylacetate: 99/1) 1.46 g of the desired product may be isolated.

Yield: 87%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.26 (m, 1H), 6.99 (m, 4H), 6.81 (d,1H), 6.68 (t, 1H), 6.57 (d, 1H), 4.35 (s, 2H), 3.80 (s, 3H), 2.86 (sbroad, 4H), 1.69 (s broad, 6H)

HPLC: 97%

MS: MH⁺ 297

Stage 2: N-(3-Methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (c)

According to the method of stage 4 of Example 1, the nitrosointermediate (376 mg) is obtained by extraction with ethyl acetate fromthe reaction medium buffered to pH 7 by using 353 mg of the previousderivative as starting product, and 477 mg of sodium nitrite in 3 mL ofacetic acid. A suspension of 180 mg of lithium aluminium hydride (4equivalents) in 5 mL of diethyl ether applied to this intermediate for 2h 30 with reflux leads to 138 mg of hydrazine after purification.

Yield: 37%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.26 (m, 1H), 6.91-7.11 (bulk aromatic,6H), 6.80 (dd, 1H), 4.56 (s, 2H), 3.80 (s, 3H), 3.12 (m, 4H), 1.59-1.79(m, 6H)

Stage 3: methyl5-bromo-2-methoxy-4-[N-(3-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoate

The product (183 mg) is obtained according to the method of stage 5 ofExample 1, by using 137 mg of the previous hydrazine as a substrate and160 mg of the acid of preparation 2 as a co-substrate in the presence of101 mg of EDCI and 16 mg of DMAP.

Yield: 70%

HPLC: 100%

MS: MH⁺ 596/598

Stage 4:5-bromo-2-methoxy-4-[N-(3-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (3)

The product (152 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 82%

MP: 109-112° C.

Elementary analysis calculated for C₂₉H₃₂BrN₃O₅.1HCl.1.5H₂O: C, 53.92;H, 5.62; N, 6.50. Found: C, 54.08; H, 5.67; N, 5.79.

HPLC: 100%

MS: MH⁺ 582/584

EXAMPLE 44-[N(4-benzyloxy-phenyl)-N(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (4) Stage 1:(4-Benzyloxy-phenyl)-(2-nitro-phenyl)-amine

To 600 μL of 2-fluoro-nitrobenzene, 6 mL of DMSO are added 1.7 g of4-(benzyloxy)aniline (1.5 equivalents) and 1.02 g of potassiumtert-butanolate (1.6 equivalents). The whole is heated to 110° C. for 1h 30. The medium is then hydrolyzed and extracted several times withethyl acetate. The organic phases are washed with a saturated solutionof sodium chloride, dried on magnesium sulfate, filtered and thenconcentrated under reduced pressure. A silica gel chromatography of theresidue (cyclohexane/ethyl acetate: 99/1) allows 754 mg of the desiredproduct to be isolated.

Yield: 41% ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.40 (s broad, 1H), 8.18 (d,1H), 7.23-7.45 (m, 6H), 7.17-7.21 (m, 2H), 7.05 (m, 3H), 6.71 (t, 1H),5.09 (s, 2H) MS: MH⁺ 321

Stage 2: N-(4-Benzyloxy-phenyl)-benzene-1,2-diamine

The product (653 mg) is obtained according to the method of stage 2 ofExample 1, by using 754 mg of the previous derivative as a startingproduct and 2.66 g of tin chloride hydrate in 12 mL of ethanol.

Yield: 95%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.68-7.37 (bulk aromatic, 13H), 5.01(s, 2H)

HPLC: 82%

MS: MH⁺ 291

Stage 3: (4-benzyloxy-phenyl)-(2-piperidin-1-yl-phenyl)-amine

To a solution of 653 mg of aniline obtained previously in 4 mL oftoluene, are successively added 940 μL of DIPEA (2.4 equivalents) and305 μL of dibromopentane (1 equivalent). The whole is refluxed for 2 hrsuntil complete disappearance of the starting aniline. After returning toroom temperature, the reaction medium is hydrolyzed and extractedseveral times with ethyl acetate. The organic phases are washed withwater, dried on magnesium sulfate, filtered and evaporated under reducedpressure. The obtained residue is purified by silica gel chromatography(cyclohexane and then cyclohexane/ethyl acetate: 99.5/0.5) leading to480 mg of the desired product.

Yield: 60%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.31-7.41 (m, 5H), 7.05-7.15 (m, 4H),6.95 (m, 3H), 6.78 (t, 3H), 6.53 (s broad, 1H), 5.06 (s, 2H)

HPLC: 94%

MS: MH⁺ 359

Stage 4: N-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine(d)

The product (202 mg) is obtained according to the method of stage 4 ofExample 1, by using 488 mg of the previous derivative as a startingproduct, and 545 mg of sodium nitrite in 5 mL of acetic acid leading tothe nitroso intermediate which is reduced by 74 mg of lithium aluminiumhydride (2 equivalents) in 5 mL of diethyl ether.

Yield: 40%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.73-7.40 (bulk aromatic, 13H), 4.94(s, 2H), 2.90 (m, 4H), 1.61 (m, 4H), 1.43 et 1.50 (m, 2H)

Stage 5: methyl4-[N-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoate

The product (193 mg) is obtained according to the method of stage 5 ofExample 1, by using 202 mg of the previous hydrazine as a substrate and180 mg of the acid from preparation 2 as a co-substrate in the presenceof 114 mg of EDCI and 20 mg of DMAP.

Yield: 54%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.37 (s broad, 1H), 7.98 (d, 1H),7.30-7.37 (m, 5H), 7.05-7.30 (m, 2H), 6.70-6.84 (m, 5H), 4.99 (d, 2H),3.68-4.08 (3s, 8H) 2.66 (m, 4H), 1.43-1.63 (m, 6H)

Stage 6:4-[N-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (4)

The product is obtained according to the method of stage 6 of Example 2,by using as a substrate the product obtained in the previous stage. Witha purification by reversed phase chromatography (conditions: C18 column,21.2×150 mm, isocratic mode 30% acetonitrile/H₂O+0.05% TFA, flow rate:15 mL/min, wavelengths: 220 and 254 nm) followed by a treatment with a 1N hydrochloric acid solution, the desired product was able to beisolated as a hydrochloride (40 mg).

Yield: 21%

MP: 114° C.

HPLC: 98%

MS: MH⁺ 644/646

EXAMPLE 5 5-bromo-4-{N[4-(4-fluoro-phenoxy)-phenyl]-N(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoicacid hydrochloride (5) Stage 1: 1-Nitro-4-(4-fluoro-phenoxy)-benzene

To a solution of 1.5 mL of 4-fluoronitrobenzene in 28 mL ofdimethylformamide are successively added 1.75 g of 4-fluoronitrobenzene(1.1 equivalents) and 2.15 g of potassium carbonate (1.1 equivalents).The whole is heated to 150° C. for 4 h 30. After returning to roomtemperature, the medium is poured on ice and put under stirring for 30min. A precipitate is formed which is filtered, rinsed with water andthen dried (3.02 g).

Yield: 91%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.20 (d, 2H), 6.97-7.16 (bulk aromatic,6H)

Stage 2: 4-(4-fluoro-phenoxy)-phenylamine

To a solution of 3.02 of the product obtained in the previous stage in50 mL of ethanol are added 14.6 g of tin chloride hydrate (5equivalents). The whole is refluxed for 1 hr. After returning to roomtemperature, the medium is poured on ice, basified to a pH of 10 bymeans of a 4 N soda solution and extracted with ethyl acetate severaltimes. The collected organic phases are dried on magnesium sulfate,filtered and evaporated under reduced pressure leading to 2.6 g of theexpected product.

Yield: quantitative

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.82-7.03 (bulk aromatic, 6H),6.71-6.79 (m, 2H)

MS: MH⁺ 204

Stage 3: [4-(4-fluoro-phenoxy)-phenyl]-(2-nitro-phenyl)-amine

The product (790 mg) is obtained according to the method of stage 1 ofExample 4, by using 900 μL of 2-fluoro-nitrobenzene and 2.6 g of theproduct obtained in the previous stage in the presence of 1.53 g ofpotassium tert-butanolate in 9 mL of DMSO.

Yield: 28%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.46 (s broad, 1H), 8.25 (d, 1H), 7.42(t, 1H), 7.28 (m, 2H), 7.05-7.19 (bulk aromatic, 7H), 6.77 (t, 1H)

HPLC: 92%

MS: MH⁺ 325

Stage 4: N-[4-(4-fluoro-phenoxy)-phenyl]-benzene-1,2-diamine

The product (637 mg) is obtained according to the method of stage 2 ofExample 1, by using 750 mg of the previous derivative as a startingproduct and 2.61 g of tin chloride hydrate in 12 mL of ethanol.

Yield: 93%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.17-7.13 (bulk aromatic, 12H)

HPLC: 92%

MS: MH⁺ 295

Stage 5: [4-(4-fluoro-phenoxy)-phenyl]-(2-piperidin-1-yl-phenyl)-amine

The product (715 mg) is obtained according to the method of stage 3 ofExample 4, by using 635 mg of the previous derivative as a startingproduct, 294 μM of dibromopentane and 905 μL of DIPEA in 4 mL oftoluene.

Yield: 91%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.79-7.26 (bulk aromatic, 12H), 6.63 (sbroad, 1H), 2.84 (m, 4H), 1.74 (m, 4H), 1.60 (m, 2H)

HPLC: 98%

MS: MH⁺ 363

Stage 6:N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine(e)

The product (275 mg) is obtained according to the method of stage 4 ofExample 1, by using 715 mg of the previous derivative as a startingproduct and 791 mg of sodium nitrite in 7 mL of acetic acid leading tothe nitroso intermediate which is reduced by 150 mg of lithium aluminiumhydride (2 equivalents) in 7 mL of diethyl ether.

Yield: 37%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.83-7.19 (bulk aromatic, 12H), 3.00(m, 4H), 1.73 (m, 4H), 1.58 (m, 2H)

Stage 7: methyl5-Bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoate

The product (336 mg) is obtained according to the method of stage 5 ofExample 1, by using 275 mg of the previous hydrazine as a substrate and243 mg of the acid of preparation 2 as a co-substrate in the presence of154 mg of EDCI and 27 mg of DMAP.

Yield: 69%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.35 (s broad, 1H), 7.98 (d, 1H),6.73-7.50 (bulk aromatic, 13H), 3.69-4.13 (3s, 8H), 2.72 (m, 4H),1.46-1.60 (m, 6H)

HPLC: 95%

MS: MH⁺ 662/664

Stage 8:5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoicacid hydrochloride (5)

The product is obtained according to the method of stage 6 of Example 2,by using as a substrate the product obtained in the previous stage. Witha purification by reversed phase chromatography of a fraction(conditions: C18 column, 21.2×150 mm, isocratic mode 30%acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min, wave lengths 220 and254 nm) followed by a treatment with a 1 N hydrochloric acid solution,the expected product was able to be isolated as a hydrochloride (43 mg).

Estimated yield: 44%

MP: 224-231° C.

Elementary analysis calculated for C₃₃H₃₁BrFN₃O₅.1HCl.1H₂O: C, 56.38; H,4.88; N, 5.98. Found: C, 56.28; H, 4.91; N, 5.78.

HPLC: 98%

MS: MH⁺ 648/650

EXAMPLE 65-bromo-2-methoxy-4-{N-[2-(4-methoxyphenyl)-ethyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-benzoicacid hydrochloride (6) Stage 1:[2-(4-Methoxy-phenyl)-ethyl]-(2-piperidin-1-yl-phenyl)-amine

To 1 g of 2-piperidinoaniline in 10 mL of DMF are added 1.72 mL of4-methoxyphenethyl chloride (2 equivalents) and 2.35 g of potassiumcarbonate (3 equivalents). The whole is heated to 100° C. for 60 hrs andthen poured on ice and extracted with ethyl acetate. The organic phasewashed with a saturated solution of sodium chloride is dried onmagnesium sulfate, filtered and evaporated under reduced pressure. Withseveral silica gel chromatographies of the residue (petroleum ether,petroleum ether/ethyl acetate: 98/2), 255 mg of the desired product wereable to be isolated.

Yield: 14%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.17 (d, 2H), 6.99 (m, 2H), 6.86 (m,2H), 6.66 (m, 2H), 4.77 (s broad, 1H), 3.80 (s, 3H), 3.36 (t, 2H), 2.90(t, 2H), 2.72 (s broad, 4H), 1.57 (m, 6H)

Stage 2:N-[2-(4-methoxy-phenyl)-ethyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine (f)

The product (160 mg) is obtained according to the method of stage 4 ofExample 1, by using 250 mg of the previous derivative as a startingproduct and 322 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 103 mg of lithium aluminiumhydride (4 equivalents) in 3 mL of tetrahydrofurane with reflux.

Yield: 61%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.80-7.38 (bulk aromatic, 8H), 3.77 (s,3H), 3.42 (t, 2H), 3.08 (t, 2H), 2.93 (m, 4H), 1.55-1.70 (m, 6H)

HPLC: 88%

MS: MH⁺ 326

Stage 3: methyl5-Bromo-2-methoxy-4-{N-[2-(4-methoxy-phenyl)-ethyl]-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl}-benzoate

To a solution of 160 mg of the previous compound in 3 mL ofdimethylformamide, are added 164 mg of the acid of preparation 2 (1.1equivalents), 104 mg of EDCI (1.1 equivalents) and 73 mg of HOBt (1.1equivalents). The reaction medium is stirred at room temperature for 30min and then heated to 40° C. for 1 h 30. The reaction crude product ispoured on ice and extracted with ethyl acetate several times. Thecollected organic phases are dried on magnesium sulfate, filtered andevaporated under reduced pressure. A first silica gel chromatography ofthe residue (petroleum ether/ethyl acetate: 95/5, 80/20 and then 50/50)was able to isolate the product which is then purified by reversed phasechromatography (conditions: C18 column, 21.2×150 mm, isocratic mode 30%acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min, wavelengths: 220 and254 nm) leading to 90 mg of the desired product as a TFA salt.

Yield: 25%

¹H NMR (DMSO, 300 MHz) δ (ppm): 12.15 (s broad, 1H), 11.53 (s, 1H), 8.06(d, 1H), 7.92 (s, 1H), 7.54 (t, 1H), 7.42 (m, 1H), 7.32 (d, 1H), 7.03(d, 3H), 6.76 (d, 2H), 3.86 and 3.83 (2s, 10H), 3.73 (s, 2H), 3.47 (s,3H), 2.98 (m, 2H), 2.85 (t, 2H), 1.79 (m, 4H), 1.34 (m, 2H)

HPLC: 99%

MS: MH⁺ 610/612

Stage 4:5-bromo-2-methoxy-4-{N-[2-(4-methoxy-phenyl)-ethyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-benzoicacid hydrochloride (6)

The product (63 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 68%

MP: 162-176° C.

Elementary analysis calculated for: C₃₀H₃₄BrN₃O₅.1HCl.1.5H₂O: C, 54.59;H, 5.80; N, 6.37. Found: C, 54.65; H, 5.31; N, 5.85.

HPLC: 90%

MS: MH⁺ 596/598

EXAMPLE 75-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoicacid hydrochloride (7) Stage 1:(4-methoxy-phenyl)-(2-methyl-6-nitro-phenyl)-amine

The product (487 mg) is obtained according to the method of stage 1 ofExample 4, by using 1 g of 2-fluoro-3-methyl-nitrobenzene and 1.19 g of4-methoxyaniline in the presence of 1.16 g of potassium tert-butanolatein 9 mL of DMSO.

Yield: 29%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.99 (d, 1H), 7.37 (m, 1H), 6.96 (t,1H), 6.78 (m, 4H), 3.78 (s, 3H), 1.99 (s, 3H)

Stage 2: N²-(4-methoxy-phenyl)-3-methyl-benzene-1,2-diamine

The product (428 mg) is obtained according to the method of stage 2 ofExample 1, by using 487 mg of the previous derivative as a startingproduct and 2.13 g of tin chloride hydrate in 6 mL of ethanol.

Yield: 99%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.99 (t, 1H), 6.75 (m, 2H), 6.65 (d,2H), 6.52 (m, 2H), 3.74 (s, 3H), 2.17 (s, 3H)

Stage 3: (4-methoxy-phenyl)-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (250 mg) is obtained according to the method of stage 3 ofExample 4, by using 425 mg of the previous derivative as a startingproduct, 253 μL of dibromopentane and 778 μL of DIPEA in 8 mL oftoluene.

Yield: 45%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.95 (m, 3H), 6.78 (m, 2H), 6.67 (m,2H), 3.77 (s, 3H), 2.73 (m, 4H), 2.10 (s, 3H), 1.59 (m, 6H)

Stage 4:N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine (g)

According to the method of stage 4 of Example 1, the nitrosointermediate (270 mg) is obtained by extraction with dichloromethanefrom the reaction medium buffered to pH 7 by using 250 mg of theprevious derivative as a starting product and 337 mg of sodium nitritein 3 mL of acetic acid. A suspension of 126 mg of lithium aluminiumhydride (4 equivalents) in 3 mL of tetrahydrofurane applied to thisintermediate for 1 hr with reflux is able to lead to 129 mg of hydrazineafter purification.

Yield: 49%

MS: MH⁺ 312

Stage 5: methyl5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-benzoate(7a)

To a solution of 129 mg of the acid obtained in preparation 2 (1.1equivalents) in 4 mL of dichloromethane are added 100 μL of thionylchloride (3.3 equivalents) and 1 drop of dimethylformamide. The whole isstirred for 1 hr at room temperature and then evaporated under reducedpressure. To the thereby obtained acid chloride, taken up in 4 mL oftoluene, are successively added a solution of 129 mg of the previoushydrazine in 3 mL of toluene and 65 μL of triethylamine (1.1equivalents). The medium is heated overnight to 40° C. and then afterreturning to room temperature, hydrolyzed and extracted with ethylacetate several times. The collected organic phases are washed withwater, dried on magnesium sulfate, filtered and evaporated under reducedpressure. The obtained residue is purified by reversed phasechromatography (conditions: C18 column, 21.2×150 mm, isocratic mode 35%acetonitrile/H₂O+0.05% TFA, flow rates: 15 mL/min, wavelengths: 220 and254 nm) leading to 110 mg of the expected product as a TFA salt.

Yield: 37%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 12.52 (s broad, 1H), 11.12 (s, 1H),7.98 (s, 1H), 7.51 (m, 2H), 7.36 (d, 1H), 7.13 (s, 1H), 6.79 (d, 2H),6.56 (d, 2H), 4.03 (m, 2H), 3.89 (s, 6H), 3.75 (s, 3H), 3.42 (m, 3H),3.06 (m, 1H), 2.26 (s, 3H), 1.79-2.01 (m, 5H), 1.50 (m, 1H)

HPLC: 93%

MS: MH⁺ 596/598

Stage 6:5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoicacid hydrochloride (7)

The product (61 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 53%

MP: 155-168° C.

Elementary analysis calculated for C₂₉H₃₂BrN₃O₅.1HCl.1.75H₂O: C, 53.55;H, 5.66; N, 6.46. Found: C, 53.28; H, 5.69; N, 6.12.

HPLC: 100%

MS: MH⁺ 582/584

EXAMPLE 85-bromo-2-methoxy-4-[N-(4-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (8) Stage 1:(4-methoxy-benzyl)-(2-piperidin-1-yl-phenyl)-amine

The product (644 mg) is obtained according to the method of stage 1 ofExample 3, by using 1 g of 2-piperidinoaniline, 982 μL of4-methoxybenzyl bromide (1.2 equivalents) and 1.6 g of potassiumcarbonate (2 equivalents) in 10 mL of DMF.

Yield: 40%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.42 (d, 2H), 7.11 (m, 2H), 7.01 (d,2H), 6.81 (td, 1H), 6.75 (dd, 1H), 4.41 (s, 2H), 3.88 (s, 3H), 2.99 (sbroad, 4H), 1.82 (m, 6H)

HPLC: 100%

MS: MH⁺ 297

Stage 2: N-(4-Methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (h)

The product (275 mg) is obtained according to the method of stage 4 ofExample 1, by using 290 mg of the previous derivative as a startingproduct and 392 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 140 mg of lithium aluminiumhydride (4 equivalents) in 4 mL of tetrahydrofurane with reflux.

Yield: 90%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.23 (m, 2H), 7.10 (m, 1H), 7.00 (m,3H), 6.87 (m, 2H), 4.47 (s, 2H), 3.82 (s, 3H), 3.10 (m, 4H), 1.59-1.77(m, 6H)

HPLC: 96%

MS: MH⁺ 312

Stage 3: methyl5-bromo-2-methoxy-4-[N-(4-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoate

The product is obtained according to the method of stage 5 of Example 7,by using 161 mg of the acid of preparation 2 and 116 μL of thionylchloride in the presence of a drop of dimethylformamide for forming theacid chloride and 150 mg of the previous hydrazine in the presence of 74μL of triethylamine for coupling. With a purification by reversed phasechromatography (conditions: C18 column, 21.2×150 mm, isocratic mode 35%acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min, wavelengths: 220 and254 nm) 80 mg of the expected product was able to be isolated as a TFAsalt.

Yield: 23%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 11.90 (s broad), 10.57 (s, 1H), 8.13(d, 1H), 7.87 (s, 1H), 7.63 (t, 1H), 7.48 (t, 1H), 7.34 (d, 1H), 7.12(d, 2H), 6.76 (m, 3H), 4.47 (m, 2H), 3.89 (m, 1H), 3.78, 3.86 and 3.89(3s, 9H), 3.64 (s, 2H), 2.95-3.15 (m, 3H), 1.93 and 2.09 (2m, 5H), 1.49(m, 1H)

HPLC: 93%

MS: MH⁺ 596/598

Stage 4:5-bromo-2-methoxy-4-[N-(4-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (8)

The product (36 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 43%

MP: 140-171° C.

Elementary analysis calculated for C₂₉H₃₂BrN₃O₅.1HCl.1.75H₂O: C, 53.55;H, 5.66; N, 6.46. Found: C, 53.52; H, 5.58; N, 5.97.

HPLC: 98%

MS: MH⁺ 582/584

EXAMPLE 95-bromo-4-[N-(4-cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride (9) Stage 1:(4-cyclohexyl-phenyl)-(2-nitro-phenyl)-amine

The product (280 mg) is obtained according to the method of stage 1 ofExample 4, by using 400 μL of 2-fluoro-nitrobenzene and 1 g of4-cyclohexylaniline in the presence of 683 mg of potassiumtert-butanolate in 4 mL of DMSO.

Yield: 25%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.47 (s broad, 1H), 8.19 (d, 1H), 7.71(d, 1H), 7.45 (t, 1H), 7.34 (t, 1H), 7.10-7.24 (m, 3H), 6.71 (t, 1H),2.53 (m, 1H), 1.35-1.95 (2m, 10H)

HPLC: 87%

MS: MH⁺ 297

Stage 2: N-(4-cyclohexyl-phenyl)-benzene-1,2-diamine

The product (154 mg) is obtained according to the method of stage 2 ofExample 1, by using 280 mg of the previous derivative as startingproduct and 1.07 g of tin chloride hydrate in 4 mL of ethanol.

Yield: 61%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.95-7.12 (m, 4H) 6.68-6.82 (m, 4H),2.40 (m, 1H), 1.40 and 1.80 (2m, 10H)

HPLC: 91%

MS: MH⁺ 267

Stage 3: (4-cyclohexyl-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (395 mg) is obtained according to the method of stage 3 ofExample 4, by using 700 mg of the preceding derivative as a startingproduct, 357 μL of dibromopentane and 1.1 mL of DIPEA in 10 mL oftoluene.

Yield: 45%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.30 (m, 1H), 7.05-7.16 (m, 5H), 6.97(t, 1H), 6.80 (t, 1H), 6.64 (s broad, 1H), 2.82 (m, 4H), 2.45 (m, 1H),1.35-1.90 (m, 16H)

Stage 4: N-(4-Cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine(i)

The product (80 mg) is obtained according to the method of stage 4 ofExample 1, by using 200 mg of the preceding derivative as startingproduct and 240 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 181 mg of lithium hydrideand aluminium (8 equivalents) in 3 mL of tetrahydrofurane in reflux.

Yield: 38%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.75-7.25 (bulk aromatic, 8H), 4.75 (sbroad), 2.97 (m, 4H), 2.42 (m, 1H), 1.25-1.90 (bulk aliphatic, 16H)

MS: MH⁺ 350

Stage 5: methyl5-bromo-4-[N-(4-cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoate

The product is obtained according to the method of stage 3 in Example 6,by using 70 mg of the previous hydrazine and 67 mg of the acid of thepreparation 2 in the presence of 42 mg of EDCI and 30 mg of HOBt in 3 mLof dimethylformamide. With a purification by reversed phasechromatography (conditions: C18 column, 21.2×150 mm, isocratic mode 50%acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min, wavelengths: 220 and254 nm) 32 mg of the expected product were able to be isolated as a TFAsalt.

Yield: 21%

HPLC: 93%

MS: MH⁺ 634/636

Stage 6:5-bromo-4-[N-(4-cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride (9)

The product (22 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the obtainedproduct from the previous stage.

Yield: 68%

MP: 163-181° C.

Elementary analysis calculated for C₃₃H₃₈BrN₃O₄.1HCl.0.75H₂O: C, 59.11;H, 6.09; N, 6.27. Found: C, 59.23; H, 6.25; N, 6.03.

HPLC: 93%

MS: MH⁺ 620/622

EXAMPLE 105-bromo-2-methoxy-4-[N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (10) Stage 1:(2-methyl-6-nitro-phenyl)-(4-trifluoromethoxy-phenyl)-amine

The product (1.92 g) is obtained as a hydrochloride according to themethod of stage 1 of Example 4, by using 1 g of2-fluoro-3-methyl-nitrobenzene and 1.3 mL of 4-trifluoromethoxy-anilinein the presence of 1.16 g of potassium tert-butanolate in 10 mL of DMSO.

Yield: 95%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.19 (s broad), 7.97 (d, 1H), 7.45 (d,1H), 7.10 (m, 3H), 6.74 (d, 2H), 2.11 (s, 3H)

HPLC: 75%

MS: MH⁺ 313

Stage 2: 3-methyl-N²-(4-trifluoromethoxy-phenyl)-benzene-1,2-diamine

The product (901 mg) is obtained according to the method of stage 2 ofExample 1, by using 1.92 g of the preceding derivative as a startingproduct and 6.94 g of tin chloride hydrate in 25 mL of ethanol.

Yield: 52%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.07 (m, 3H), 6.73 (m, 2H), 6.53 (d,2H), 5.10 (s broad, 1H), 3.99 (s broad, 2H), 2.18 (s, 3H)

HPLC: 90%

MS: MH⁺ 283

Stage 3:(2-methyl-6-piperidin-1-yl-phenyl)-(4-trifluoromethoxy-phenyl)-amine

The product (890 mg) is obtained according to the method of stage 3 inExample 4, by using 900 mg of the preceding derivative as startingproduct, 433 μL of dibromopentane and 1.3 mL of DIPEA in 15 mL oftoluene.

Yield: 79%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.04 (m, 3H), 6.95 (d, 2H), 6.66 (d,2H), 6.19 (s broad, 1H), 2.72 (m, 4H) 2.11 (s, 3H), 1.56 (m, 6H)

HPLC: 96%

MS: MH⁺ 351

Stage 4:N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazine(j)

The product (270 mg)—contaminated by the starting amine—is obtainedaccording to stage 4 of Example 1, by using 450 mg of the precedingderivative as a starting product and 514 mg of sodium nitrite in 4 mL ofacetic acid leading to the nitroso intermediate which is reduced by 355mg of lithium aluminium hydride (8 equivalents) in 4 mL oftetrahydrofurane with reflux.

Estimated yield: 23%

MS: MH⁺ 366

Stage 5: methyl5-bromo-2-methoxy-4-[N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazinocarbonylmethyl]-benzoate

The product is obtained according to the method of stage 3 of Example 6,by using 400 mg of the preceding hydrazine and 365 mg of the acid ofpreparation 2 in the presence of 231 mg of EDCI and 163 mg of HOBt in 4mL of dimethylformamide. With purification by reversed phasechromatography (conditions: C18 column, 21.2×150 mm, isocratic mode 35%acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min, wavelengths: 220 and254 nm) it was possible to isolate 260 mg of the expected product as aTFA salt.

Yield: 36%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 12.26 (s broad, 1H) 11.42 (s, 1H), 7.94(s, 1H), 7.50 (m, 3H), 7.09 (m, 3H), 6.62 (d, 2H), 4.02 (m, 2H), 3.87(s, 6H), 3.60 (m, 1H), 3.31 (m, 2H), 3.15 (m, 1H), 2.24 (s, 3H), 2.14(m, 1H), 1.79-1.94 (m, 4H), 1.52 (m, 1H)

HPLC: 95%

MS: MH⁺ 650/652

Stage 6:5-bromo-2-methoxy-4-[N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazino-carbonylmethyl]-benzoicacid hydrochloride (10)

The product (166 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 62%

MP: 128° C. (decomposition)

Elementary analysis calculated for C₂₉H₂₉BrF₃N₃O₅.1HCl.1H₂O: C, 50.41;H, 4.67; N, 6.08. Found: C, 50.02; H, 4.68; N, 5.82.

HPLC: 96%

MS: MH⁺ 636/638

EXAMPLE 115-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-benzoicacid hydrochloride (11) Stage 1: (4-bromo-phenyl)-(2-nitro-phenyl)-amine

The product (6.49 g) is obtained according to the method of stage 1 ofExample 4, by using 3.73 mL of 2-fluoro-nitrobenzene and 7.31 g of4-bromoaniline in the presence of 6.36 g of potassium tert-butanolate in120 mL of DMSO.

Yield: 62%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.38 (s broad, 1H), 8.19 (d, 1H), 7.51(d, 2H), 7.38 (t, 1H), 7.17 (t, 3H), 6.81 (t, 1H)

HPLC: 99%

MS: MH⁺ 293/295

Stage 2: N-(4-bromo-phenyl)-benzene-1,2-diamine

The product (571 mg) is obtained according to the method of stage 2 ofExample 1, by using 723 mg of the previous derivative as a startingproduct and 2.78 g of tin chloride hydrate in 7 mL of ethanol.

Yield: 88%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.26 (d, 2H), 7.05 (m, 2H), 6.78 (m,2H), 6.60 (d, 1H)

HPLC: 97%

MS: MH⁺ 263/265

Stage 3: (4-bromo-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (1.03 g) is obtained according to the method of stage 3 ofExample 4, by using 1.35 g of the previous derivative as a startingproduct, 698 μL of dibromopentane and 2.1 mL of DIPEA in 13 mL oftoluene.

Yield: 61%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.36 (m, 2H), 7.26 (m, 1H), 7.01-7.10(m, 4H), 6.89 (m, 1H), 6.56 (s broad, 1H), 2.82 (t, 4H), 1.57-1.74 (m,6H)

HPLC: 100%

MS: MH⁺ 331/33

Stage 4: (4′-methoxy-biphenyl-4-yl)-(2-piperidin-1-yl-phenyl)-amine

To a solution of 554 mg of the brominated derivative obtained previouslyin 14 mL of a 50:50 methanol/toluene mixture are successively added 380mg of phenylboronic acid (1.5 equivalents), 96 mg of palladium tetrakis(0.05 equivalents), 212 mg of lithium chloride (3 equivalents) and 4.17mL of a 1 molar solution of calcium carbonate. The whole is refluxed for2 hrs. The reaction crude product is extracted with ethyl acetateseveral times; the collected organic phases are washed with water, andthen dried on magnesium sulfate, filtered and evaporated under reducedpressure.

The obtained residue is purified by silica gel chromatography (petroleumether and then petroleum ether/ethyl acetate: 99/1) leading to 260 mg ofthe expected product.

Yield: 43%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.53 (m, 4H), 7.38 (dd, 1H), 7.25 (m,2H), 7.12 (dd, 1H), 6.97-7.10 (m, 3H), 6.88 (td, 1H), 6.76 (s broad,1H), 3.86 (s, 3H), 2.87 (t, 4H), 1.52-1.78 (m, 6H)

HPLC: 80%

MS: MH⁺ 359

Stage 5:N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (k)

The product (141 mg) is obtained according to the method of stage 4 ofExample 1, by using 203 mg of the previous derivative as a startingproduct and 226 mg of sodium nitrite in 1.5 mL of acetic acid leading tothe nitroso intermediate which is reduced by 179 mg of lithium aluminiumhydride (8 equivalents) in 4 mL of tetrahydrofurane with reflux.

Yield: 64%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.49 (d, 2H), 7.38 (d, 2H), 7.14 (m,2H), 6.93 (m, 4H), 6.87 (d, 2H), 3.84 (s, 3H), 2.92 (m, 4H), 1.39 (m,6H)

HPLC: 90%

MS: MH⁺ 374

Stage 6: methyl5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-benzoate

The product is obtained according to the method of stage 3 of Example 6,by using 141 mg of the previous hydrazine and 126 mg of the acid ofpreparation 2 in the presence of 79 mg of EDCI and 56 mg of HOBt in 6 mLof dimethylformamide. With a purification by reversed phasechromatography (conditions C18 column, 21.2×150 mm, isocratic mode 50%acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min, wavelengths: 220 and254 nm), 9 mg of the expected product were able to be isolated as a TFAsalt.

Yield (non-optimized): 3%

HPLC: 75%

MS: MH⁺ 658/660

Stage 7:5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl]-benzoicacid hydrochloride (11)

The product (7.3 mg) is obtained as a hydrochloride according to themethod of stage 6 or Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 92%

HPLC: 80%

MS: MH⁺ 644/646

EXAMPLE 125-bromo-4-[N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-2-methoxy-benzoicacid hydrochloride (12) Stage 1: 1-cyclohexyloxy-4-nitro-benzene

To 3.9 g of cyclohexanol (1.1 equivalents) put into the presence of 2.12g of sodium hydride (1.5 equivalents) under stirring for 10 min, isadded a solution of 5 g of 4-fluoronitrobenzene in 75 mL ofdimethylformamide. The whole is heated to 60° C. for 5 hrs. Afterreturning to room temperature, the medium is hydrolyzed and the reactioncrude product is extracted with ethyl acetate several times. The organicphases are dried on magnesium sulfate, filtered and evaporated underreduced pressure. With a silica gel chromatography of the residue(cyclohexane and then cyclohexane/ethyl acetate: 98/2 and 90/10) 6.06 gof the desired product are able to be isolated.

Yield: 78%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.16 (d, 2H), 6.92 (d, 2H), 4.37 (m,1H), 1.98 (m, 2H), 1.81 (m, 2H), 1.35-1.65 (m, 6H)

HPLC: 98%

MS: [M+Na]⁺ 244

Stage 2: 4-cyclohexyloxy-phenylamine

The product (4.48 g) is obtained according to the method of stage 2 ofExample 5, by using 6.06 g of the previous derivative as a startingproduct and 30.9 g of tin chloride hydrate in 59 mL of ethanol.

Yield: 87%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.76 (d, 2H), 6.62 (d, 2H), 4.06 (m,1H), 3.42 (s broad, 2H), 1.95 (m, 2H) 1.78 (m, 2H), 1.28-1.60 (m, 6H)

HPLC: 88%

MS: MH⁺ 192

Stage 3: (4-cyclohexyloxy-phenyl)-(2-nitro-phenyl)-amine

The product (4.27 g) is obtained according to the method of stage 1 ofExample 4, by using 2.95 mL of 2-fluoro-nitrobenzene and 4.48 g of theproduct obtained in the previous stage in the presence of 4.18 g ofpotassium tert-butanolate in 108 mL of DMSO.

Yield: 59%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.40 (s broad, 1H), 8.20 (d, 1H), 7.35(m, 1H), 7.18 (m, 2H), 6.95-7.05 (m, 3H), 6.72 (m, 1H), 4.06 (m, 1H),2.05 (m, 2H), 1.82 (m, 2H), 1.35-1.60 (m, 6H)

HPLC: 86%

MS: MH⁺ 313

Stage 4: N-(4-cyclohexyloxy-phenyl)-benzene-1,2-diamine

The product (3.43 g) is obtained according to the method of stage 2 ofExample 1, by using 4.27 g of the previous derivative as a startingproduct and 15.42 g of tin chloride hydrate in 27 mL of ethanol.

Yield: 88%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.04 (d, 1H), 6.94 (m, 1H), 6.72-6.84(m, 6H), 4.14 (m, 1H), 1.97 (m, 2H), 1.80 (m, 2H), 1.30-1.60 (m, 6H)HPLC: 92%

MS: MH⁺ 283

Stage 5: (4-cyclohexyloxy-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (1.55 g) is obtained according to the method of stage 3 ofExample 4, by using 3.43 g of the previous derivative as a startingproduct, 1.65 mL of dibromopentane and 5.1 mL of DIPEA in 49 ml oftoluene.

Yield: 36%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.07 (m, 4H), 6.80-6.98 (m, 3H), 6.78(m, 1H), 6.52 (s broad, 1H), 4.21 (m, 1H), 2.86 (m, 4H), 1.35-2.05 (m,16H)

HPLC: 99%

MS: MH⁺ 351

Stage 6:N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (I)

The product (118 mg) is obtained according to the method of stage 4 ofExample 1, by using 500 mg of the previous derivative as a startingproduct and 571 mg of sodium nitrite in 4 mL of acetic acid leading tothe nitroso intermediate which is reduced by 431 mg of lithium aluminiumhydride (8 equivalents) in 4 mL of tetrahydrofurane with reflux.

Yield: 23%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.00-7.18 (m, 5H) 6.94 (m, 1H), 6.90(m, 2H), 4.77 (s broad, 1H), 4.09 (m, 1H), 2.98 (m, 4H), 2.00 (m, 2H),1.80 (m, 2H), 1.24-1.67 (m, 12H)

HPLC: 94%

MS: MH⁺ 366

Stage 7: methyl5-bromo-4-[N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoate

The product is obtained according to the method of stage 3 of Example 6,by using 50 mg of the previous hydrazine and 46 mg of the acid ofpreparation 2 in the presence of 29 mg of EDCI and 20 mg of HOBt in 1.5mL of dimethylformamide. With a purification by reversed phasechromatography of a fraction (conditions; C18 column, 21.2×150 mm,isocratic mode 45% acetonitrile/H₂O+0.05% TFA, flow rate: 15 mL/min,wavelengths: 220 and 254 nm) 57 mg of the expected product were able tobe isolated as a TFA salt.

Estimated yield: 54%

HPLC: 92%

MS: MH⁺ 650/652

Stage 8:5-bromo-4-[N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride (12)

The product (61 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 85%

MP: 145-180° C.

HPLC: 91%

MS: MH⁺ 636/638

EXAMPLE 135-bromo-2-methoxy-4-[N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoicacid hydrochloride (13) Stage 1:(2-nitro-phenyl)-(4-phenoxy-phenyl)-amine

The product (2.03 g) is obtained according to the method of stage 1 ofExample 4, by using 3.7 mL of 2-fluoro-nitrobenzene and 7.88 g of4-phenoxyaniline in the presence of 6.36 g of potassium tert-butanolatein 34 mL of DMSO.

Yield: 18%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.44 (s broad, 1H), 8.20 (d, 1H), 7.37(m, 3H), 7.25 (m, 2H), 7.05-7.18 (m, 6H), 6.76 (m, 1H)

HPLC: 80%

MS: MH⁺ 307

Stage 2: N-(4-phenoxy-phenyl)-benzene-1,2-diamine

The product (709 mg) is obtained by catalytic hydrogenation in thepresence of 203 mg of 10% palladium on charcoal in 40 mL of ethanol.

Yield: 38%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.30 (m, 2H), 6.90-7.12 (m, 7H),6.70-6.85 (m, 4H)

HPLC: 100%

MS: MH⁺ 277

Stage 3: (4-phenoxy-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (799 mg) is obtained according to the method of stage 3 ofExample 4, by using 709 mg of the previous derivative as a startingproduct, 350 μL of dibromopentane and 1.07 mL of DIPEA in 10 mL oftoluene.

Yield: 82%

¹H NMR (DMSO, 300 MHz) δ (ppm): 7.40 (d, 1H), 7.25 (m, 4H), 7.03 (m,4H), 6.95 (m, 4H), 3.37 (m, 4H), 1.90 (m, 4H), 1.61 (m, 2H)

HPLC: 100%

MS: MH⁺ 345

Stage 4: N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (m)

The product (185 mg) is obtained according to the method of stage 4 ofExample 1, by using 400 mg of the previous derivative as a startingproduct and 420 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 319 mg of lithium aluminiumhydride (8 equivalents) in 3 mL of tetrahydrofurane with reflux.

Yield: 49%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.92-7.26 (m, 13H), 4.82 (s broad, 2H),2.97 (m, 4H), 1.55-1.69 (2m, 6H)

HPLC: 97%

MS: MH⁺ 360

Stage 5: methyl5-bromo-2-methoxy-4-[N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoate

The product (270 mg) is obtained according to the method of stage 3 ofExample 6, by using 185 mg of the previous hydrazine and 172 mg of theacid of the preparation 2 in the presence of 108 mg of EDCI and 76 mg ofHOBt in 3 mL of dimethylformamide.

Yield: 81%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.35 (s broad, 1H) 7.97 (d, 1H),6.75-7.50 (bulk aromatic, 14H), 3.70-3.94 (3s, 8H), 2.68 (m, 4H),1.46-1.59 (m, 6H)

HPLC: 77%

MS: MH⁺ 644/646

Stage 6:5-bromo-2-methoxy-4-[N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (13)

The product is obtained according to the method of stage 6 of Example 2,by using as a substrate the product obtained in the previous stage. Withpurification by reversed phase chromatography of a fraction (conditions:C18 column, 21.2×150 mm, isocratic mode 35% acetonitrile/H₂O+0.05% TFA,flow rate: 15 mL/min, wavelengths: 220 and 254 nm) followed by atreatment with a 1 N hydrochloric acid solution, the expected productwas able to be isolated as a hydrochloride (89 mg).

Yield: 32%

MP: 232-235° C.

Elementary analysis calculated for C₃₃H₃₂BrN₃O₅.1HCl.1H₂O: C, 57.86; H,5.15; N, 6.13. Found: C, 57.74; H, 5.01; N, 5.89.

HPLC: 97%

MS: MH⁺ 630/632

EXAMPLE 145-bromo-4-{N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoicacid hydrochloride (14) Stage 1:[4-(4-chloro-phenoxy)-phenyl]-(2-nitro-phenyl)-amine

The product (609 mg) is obtained according to the method of stage 1 ofExample 4, by using 840 μL of 2-fluoro-nitrobenzene and 2.1 g of4-(chlorophenoxy)-aniline in the presence of 1.43 g of potassiumtert-butanolate in 20 mL of DMSO.

Yield: 22%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.21 (d, 1H), 7.24-7.40 (m, 5H),6.97-7.14 (m, 5H), 6.77 (t, 1H)

HPLC: 97%

MS: MH⁺ 341/343

Stage 2: N-[4-(4-chloro-phenoxy)-phenyl]-benzene-1,2-diamine

The product (524 mg) is obtained according to the method of stage 2 ofExample 1, by using 609 mg of the previous derivative as a startingproduct and 2 g of tin chloride hydrate in 10 mL of ethanol.

Yield: 94%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.73-7.38 (bulk aromatic, 12H)

HPLC: 100%

MS: MH⁺ 311/313

Stage 3: [4-(4-Chloro-phenoxy)-phenyl]-(2-piperidin-1-yl-phenyl)-amine

The product (596 mg) is obtained according to the method of stage 3 ofExample 4, by using 684 mg of the previous derivative as a startingproduct, 300 μL of dibromopentane and 920 μL of DIPEA in 15 mL oftoluene.

Yield: 71%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.80-7.28 (bulk aromatic, 12H), 6.66 (sbroad, 1H), 2.86 (m, 4H), 1.72 (m, 4H), 1.61 (m, 2H)

HPLC: 99%

MS: MH⁺ 379/381

Stage 4:N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine(n)

The product (80 mg) is obtained according to the method of stage 4 ofExample 1, by using 300 mg of the previous derivative as a startingproduct and 317 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 120 mg of lithium aluminiumhydride (4 equivalents) in 5 mL of tetrahydrofurane.

Yield: 26%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.86-7.25 (bulk aromatic, 12H), 2.98(m, 4H), 1.70 (m, 4H), 1.56 (m, 2H)

HPLC: 83%

MS: MH⁺ 394/396

Stage 5: methyl5-bromo-4-{N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-2-methoxy-benzoate

The product (86 mg) is obtained according to the method of stage 3 ofExample 6, by using 80 mg of the previous hydrazine and 68 mg of theacid of preparation 2 in the presence of 43 mg of EDCI and 30 mg of HOBtin 3 mL of dimethylformamide.

Yield: 62%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.35 (s broad, 1H), 7.97 (d, 1H),6.75-7.52 (bulk aromatic, 13H), 3.67-3.91 (3s, 8H), 2.68 (m, 4H),1.42-1.59 (m, 6H)

HPLC: 94%

MS: MH⁺ 678/680

Stage 6:5-bromo-4-{N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl}-2-methoxy-benzoicacid hydrochloride (14)

The product (52 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 62%

MP: 153.5-163.5° C.

HPLC: 95% MS: MH⁺ 664/666

EXAMPLE 154-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-2-methoxy-benzoicacid hydrochloride (15) Stage 1:[4-(4-fluoro-phenoxy)-phenyl]-(2-methyl-6-nitro-phenyl)-amine

The product (790 mg) is obtained according to the method of stage 1 ofExample 4, by using 900 μL of 2-fluoro-3-methyl-nitrobenzene and 2.6 gof 4-(4-fluoro-phenoxy)-phenylamine obtained in stage 2 of Example 5 inthe presence of 2.36 g of potassium tert-butanolate in 80 mL of DMSO.

Yield: 40%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.38 (s broad, 1H), 1.98 (d, 1H), 7.40(d, 1H), 6.87-7.06 (bulk aromatic, 7H), 6.76 (d, 2H), 2.08 (s, 3H)

HPLC: 84%

MS: MH⁺ 339

Stage 2: N²-[4-(4-fluoro-phenoxy)-phenyl]-3-methyl-benzene-1,2-diamine

The product (1.58 g) is obtained by hydrogenation according to themethod of stage 2 of Example 13.

Yield: 87%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.83-7.01 (bulk aromatic, 7H), 6.67 (d,2H), 6.55 (d, 2H), 4.92 (s broad, 1H), 3.89 (s broad, 2H), 2.18 (s, 3H)

HPLC: 98%

MS: MH⁺ 309

Stage 3:[4-(4-fluoro-phenoxy)-phenyl]-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (1.16 g) is obtained according to the method of stage 3 ofExample 4, by using 1.58 g of the previous derivative as a startingproduct, 700 μL of dibromopentane and 2.14 mL of DIPEA in 30 mL oftoluene.

Yield: 60%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.84-7.01 (bulk aromatic, 9H), 6.70 (d,2H), 6.18 (s broad, 1H), 2.74 (m, 4H), 2.13 (s, 3H), 1.58 (m, 6H)

HPLC: 98%

MS: MH⁺ 377

Stage 4:N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine(o)

The product (198 mg) is obtained according to the method of stage 4 ofExample 1, by using 525 mg of the previous derivative as a startingproduct and 558 mg of sodium nitrite in 4 mL of acetic acid leading tothe nitroso intermediate which is reduced by 208 mg of lithium aluminiumhydride (4 equivalents) in 4 mL of tetrahydrofurane.

Yield: 36%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.83-7.18 (bulk aromatic, HH), 4.87 (sbroad, 2H), 2.68 and 2.94 (4H, 2m), 2.12 (s, 3H), 1.50-1.64 (m, 6H)

HPLC: 76%

MS: MH⁺ 392

Stage 5: methyl4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-2-methoxy-benzoate

The product (141 mg) is obtained according to the method of stage 3 ofExample 6, by using 95 mg of the previous hydrazine and 60 mg of theacid of the preparation 1 in the presence of 51 mg of EDCI and 36 mg ofHOBt in 1.5 mL of dimethylformamide.

Yield: 97%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.76 (s broad, 1H), 7.74 (d, 1H),6.50-7.22 (bulk aromatic, 13H), 3.87 (s, 3H), 3.70 (m, 5H), 2.72 (m,2H), 2.44 (s, 3H), 2.30 (m, 2H), 1.30-1.42 (2m, 6H)

HPLC: 97%

MS: MH⁺ 598

Stage 6:4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-2-methoxy-benzoicacid hydrochloride (15)

The product (131 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 90%

MP: 155-168° C.

HPLC: 100%

MS: MH⁺ 584

EXAMPLE 165-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl}-2-methoxy-benzoicacid hydrochloride (16) Stage 1: methyl5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl}-2-methoxy-benzoate(16a)

The product (154 mg) is obtained according to the method of stage 3 ofExample 6, by using 95 mg of the hydrazine of stage 4 of Example 15 and81 mg of the acid of preparation 2 in the presence of 51 mg of EDCI and36 mg of HOBt in 1.5 mL of dimethylformamide.

Yield: 94%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.86 (s broad, 1H), 7.98 (s, 1H),6.84-7.23 (bulk aromatic, 10H), 6.57 (d, 2H), 3.87 (s, 3H), 3.76 (s,2H), 3.71 (s, 3H), 2.80 (m, 2H), 2.44 (s, 5H), 1.37-1.48 (2m, 6H)

HPLC: 91%

MS: MH⁺ 676/678

Stage 2:5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-2-methoxy-benzoicacid hydrochloride (16)

The product (116 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 73%

MP: 155-168° C.

Elementary analysis calculated for C₃₄H₃₃BrFN₃O₅.1HCl.1.5H₂O: C, 56.25;H, 5.14; N, 5.79. Found: C, 56.31; H, 5.04; N, 5.61.

HPLC: 98%

MS: MH⁺ 662/664

EXAMPLE 174-[N-(4-benzyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (17) Stage 1:(4-benzyl-phenyl)-(2-nitro-phenyl)-amine

The product (621 mg) is obtained according to the method of stage 1 ofExample 4, by using 958 μL of 2-fluoro-nitrobenzene and 2 g of4-benzylaniline in the presence of 1.63 of potassium tert-butanolate in30 mL of DMSO.

Yield: 22%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.46 (s broad, 1H), 8.19 (d, 1H), 7.71(d, 1H), 7.44 (m, 1H), 7.10-7.40 (bulk aromatic, 9H), 6.74 (m, 1H), 4.01(s, 2H)

HPLC: 78%

MS: [M+Na]⁺ 327

Stage 2: N-(4-benzyl-phenyl)-benzene-1,2-diamine

The product (291 mg) is obtained by hydrogenation according to themethod of stage 2 of Example 13.

Yield: 52%

HPLC: 100%

MS: MH⁺ 275

Stage 3: (4-benzyl-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (213 mg) is obtained according to the method of stage 3 ofExample 4, by using 291 mg of the previous derivative as a startingproduct, 144 μL of dibromopentane and 444 μL of DIPEA in 4 mL oftoluene.

Yield: 59%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.79-7.32 (bulk aromatic, 13H), 6.63 (sbroad, 1H), 3.94 (s, 2H), 2.83 (m, 4H), 1.70 (m, 4H), 1.58 (m, 2H)

HPLC: 96%

MS: MH⁺ 343

Stage 4: N-(4-benzyl-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine (p)

The product (60 mg) is obtained according to the method of stage 4 ofExample 1, by using 213 mg of the previous derivative as a startingproduct and 249 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 189 mg of lithium aluminiumhydride (8 equivalents) in 3 mL of tetrahydrofurane.

Yield: 27%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.92-7.31 (bulk aromatic, 13H), 4.75 (sbroad, 1H), 3.91 (s, 2H), 2.96 (m, 4H), 1.66 (m, 4H), 1.54 (m, 2H)

HPLC: 100%

MS: MH⁺ 358

Stage 5: methyl4-[N-(4-benzyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoate

The product (64 mg) is obtained according to the method of stage 3 ofExample 6, by using 60 mg of the previous hydrazine and 56 mg of theacid of preparation 2 in the presence of 35 mg of EDCI and 25 mg of HOBtin 1 mL of dimethylformamide.

Yield: 59%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.33 (s broad, 1H), 7.98 (d, 1H),6.71-7.51 (bulk aromatic, 14H), 3.95 (s, 6H), 3.70 and 3.76 (2s, 4H),2.74 (m, 4H), 1.28-1.60 (m, 6H)

HPLC: 90%

MS: MH⁺ 642/644

Stage 6:4-[N-(4-benzyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (17)

The product (58 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 88%

MP: 137.5-162° C.

HPLC: 97%

MS: MH⁺ 628/630

EXAMPLE 184-[N-(4-bromo-phenyl)-[N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride (18) Stage 1:N-(4-bromo-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (g)

The product (370 mg) is obtained according to the method of stage 4 ofExample 1, by using 500 mg of the derivative obtained in stage 3 ofExample 11 as a starting product and 604 mg of sodium nitrite in 3 mL ofacetic acid leading to the nitroso intermediate which is reduced by 458mg of lithium aluminium hydride (8 equivalents) in 3 mL oftetrahydrofurane.

Yield: 71%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.98-7.25 (bulk aromatic, 8H), 4.77 (sbroad, 2H), 2.92 (m, 4H), 1.66 (m, 4H), 1.55 (m, 2H)

HPLC: 88%

MS: MH⁺ 346/348

Stage 2: methyl4-[N-(4-bromo-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoate

The product (64 mg) is obtained according to the method of stage 3 ofExample 6, by using 370 mg of the previous hydrazine and 304 mg of theacid of preparation 3 in the presence of 225 mg of EDCI and 159 mg ofHOBt in 5 mL of dimethylformamide.

Yield: 89%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.34 (s broad, 1H), 7.78 (d, 1H),6.63-7.49 (bulk aromatic, 9H), 3.87 (2s, 6H), 3.70 (s, 2H), 2.75 (m,4H), 1.28 et 1.60 (2m, 6H)

HPLC: 96%

MS. MH⁺ 586/588

Stage 3:4-[N-(4-bromo-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride (18)

The product (39 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 75%

MP: 177.2-189° C.

HPLC: 95%

MS: MH⁺ 572/574

EXAMPLE 194-[N-(3′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride (19) Stage 1: methyl4-[N-(3′-Acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoate

To a solution of 200 mg of the brominated derivative obtained in stage 2of Example 18 in 2 mL of a 50:50 methanol/toluene mixture aresuccessively added 84 mg of 3-acetylphenylboronic acid (1.5equivalents), 20 mg of palladium tetrakis (0.05 equivalents) and 85 μLof 1 molar solution of sodium carbonate. The whole is refluxed for 3hrs. The reaction crude product taken up in water is extracted withethyl acetate several time, the collected organic phases are washed witha 1 molar solution of soda, and then dried on magnesium sulfate,filtered and evaporated under reduced pressure. The obtained residue ispurified by silica gel chromatography (petroleum ether/ethyl acetate:90/10 and then 80/20 right up to 50/50) leading to 110 mg of theexpected product.

Yield: 51%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.35 (s, 1H), 8.04 (d, 1H), 7.74 (m,3H), 6.94-7.62 (bulk aromatic, 8H), 6.80 (m, 2H), 2.79-3.62 (3s, 8H),2.56 (m, 4H), 2.05 (s, 3H), 1.18-1.53 (m, 6H)

HPLC: 92%

MS: MH⁺ 626/628

Stage 2:4-[N-(3′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride (19)

The product (69 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 66%

MP: 140.2-165.3° C.

HPLC: 91%

MS: MH⁺ 612/614

EXAMPLE 204-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride (20) Stage 1: methyl4-[N-(4′-Acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoate

The product (167 mg) is obtained according to the method of stage 1 ofExample 19, by using as a substrate the product obtained in stage 2 ofExample 18 and as a co-substrate 4-acetylphenylboronic acid.

Yield: 78%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.35 (s, 1H), 6.70-7.91 (bulk aromatic,14H), 3.61-3.78 (3s, 8H), 2.60 (m, 4H), 2.28 (s, 3H), 1.20-1.51 (m, 6H)

HPLC: 87%

MS: MH⁺ 626/628

Stage 2:4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride (20)

The product (82 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 47%

MP: 165.3-190.1° C.

HPLC: 100%

MS: MH⁺ 612/614

EXAMPLE 215-bromo-2-methoxy-4-[N-(3-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (21) Stage 1:(2-nitro-phenyl)-(3-phenoxy-phenyl)-amine

The product (2.08 g) is obtained according to the method of stage 1 ofExample 4, by using 1.23 mL of 2-fluoronitrobenzene and 3.3 g of3-phenoxyaniline in the presence of 2.13 g of potassium tert-butanolatein 10 mL of DMSO.

Yield: 57%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.38 (s broad, 1H), 8.12 (d, 1H), 7.63(d, 1H), 6.70-7.43 (m, 11H)

HPLC: 79%

MS: MH⁺ 307

Stage 2: N-(3-phenoxy-phenyl)-benzene-1,2-diamine

The product (1.88 g) is obtained by catalytic hydrogenation in thepresence of 210 mg of 10% palladium on charcoal in 40 mL of an ethylacetate/ethanol (1:1) mixture.

Yield: quantitative

HPLC: 91%

MS: MH⁺ 277

Stage 3: (3-Phenoxy-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (1.22 g) is obtained according to the method of stage 3 ofExample 4, by using 1.88 g of the previous derivative as a startingproduct, 925 μL of dibromopentane and 2.84 mL of DIPEA in 40 mL oftoluene.

Yield: 52%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.83-7.19 (bulk aromatic, 1H), 6.72 (s,1H), 6.53 (dd, 1H), 2.81 (m, 4H), 1.50-1.74 (m, 6H)

HPLC: 100%

MS: MH⁺ 345

Stage 4: N-(3-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (r)

The product (99 mg) is obtained according to the method of stage 4 ofExample 1, by using 400 mg of the previous derivative as a startingproduct and 465 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 159 mg of lithium aluminiumhydride (4 equivalents) in 4 mL of tetrahydrofurane with reflux.

Yield: 24% ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.70-7.25 (bulk aromatic,12H), 6.28 (dd, 1H), 4.68 (s broad, 2H), 2.85 (m, 4H), 1.46-1.63 (m, 6H)

HPLC: 76%

MS: MH⁺ 360

Stage 5: methyl5-bromo-2-methoxy-4-[N-(3-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoate

The product (168 mg) is obtained according to the method of stage 3 ofExample 6, by using 99 mg of the previous hydrazine and 92 mg of theacid of preparation 2 in the presence of 58 mg of EDCI and 41 mg of HOBtin 1 mL of dimethylformamide.

Yield: 95%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.35 and 9.40 (2 s broad, 1H), 7.98(2s, 1H), 6.41-7.40 (bulk aromatic, 14H), 3.70-3.95 (3s, 8H), 2.68 (m,4H), 1.46-1.59 (m, 6H)

HPLC: 96%

MS: MH⁺ 644/646

Stage 6:5-bromo-2-methoxy-4-[N-(3-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (21)

The product (124 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 71%

MP: 142-159° C.

Elementary analysis calculated for C₃₃H₃₂BrN₃O₅.0.75HCl: C, 60.25; H,5.02; N, 6.39. Found: C, 59.98; H, 5.11; N, 6.27.

HPLC: 96%

MS: MH⁺ 630/632

EXAMPLE 225-bromo-2-methoxy-4-[N-(4-phenylsulfanyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoicacid hydrochloride (22) Stage 1: 4-phenylsulfanyl-phenylamine

To a solution of 5 g of 4-nitrophenyl sulfur in 100 mL of anethanol/ethyl acetate mixture (1:1) are added 500 mg of 10% palladium oncharcoal. The whole is placed under a hydrogen atmosphere (P=10 bars)for one night.

The whole is filtered on celite, rinsed and the filtrate is concentratedunder reduced pressure leading to 3.57 g of the expected product.

Yield: 82%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.10-7.35 (bulk aromatic, 7H), 6.69 (d,2H), 3.98 (s broad, 2H)

HPLC: 86%

MS: MH⁺ 202

Stage 2: (2-nitro-phenyl)-(4-phenylsulfanyl-phenyl)-amine

The product (2.50 g) is obtained according to the method of stage 1 ofExample 4, by using 1.25 mL of 2-fluoro-nitrobenzene and 3.57 g of theobtained product of the previous stage in the presence of 2.12 g ofpotassium tert-butanolate in 10 mL of DMSO.

Yield: 66%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.48 (s broad, 1H) 8.22 (d, 1H),7.11-7.42 (bulk aromatic, 11H), 6.83 (m, 1H),

HPLC: 96%

MS: [M+Na]⁺ 345

Stage 3: N-[4-phenylsulfanyl-phenyl]-benzene-1,2-diamine

The product (2 g) is obtained by catalytic hydrogenation by using 2.50 gof the derivative obtained previously in the presence of 250 mg of 10%palladium on charcoal in 30 mL of an ethanol/ethyl acetate mixture(1:1).

Yield: 88%

HPLC: 92%

MS: MH⁺ 293

Stage 4: (4-phenylsulfanyl-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (1.37 g) is obtained according the method of stage 3 ofExample 4, by using 2 g of the previous derivative as starting product,932 μL of dibromopentane and 2.86 mL of DIPEA in 40 mL of toluene.

Yield: 55%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.87-7.41 (bulk aromatic, 13H), 6.78 (sbroad, 1H), 2.84 (m, 4H), 1.74 (m, 4H), 1.60 (m, 2H)

HPLC: 98%

MS: MH⁺ 361

Stage 5:N-(4-phenylsulfanyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (s)

The product (300 mg) is obtained according to the method of stage 4 ofExample 1, by using 800 mg of the previous derivative as startingproduct and 888 mg of sodium nitrite in 5 mL of acetic acid leading tothe nitroso intermediate which is reduced by 316 mg of lithium aluminiumhydride (4 equivalents) in 5 mL of tetrahydrofurane.

Yield: 36%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.92-7.26 (bulk aromatic, 13H), 4.71 (sbroad, 2H), 2.84 (m, 4H), 1.58 (m, 4H), 1.47 (m, 2H)

HPLC: 90%

MS: MH⁺ 376

Stage 6: methyl5-bromo-2-methoxy-4-[N-(4-phenyl-sulfanyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-benzoate

The product (340 mg) is obtained according to the method of stage 3 ofExample 6, by using 300 mg of the previous hydrazine as substrate and266 mg of the acid of preparation 2 as a co-substrate in the presence of168 mg of EDCI and 118 mg of HOBt in 2.5 mL of dimethylformamide.

Yield: 64%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.34 (s broad, 1H) 7.99 (2s, 1H),6.79-7.53 (bulk aromatic, 14H), 3.70-3.92 (3s, 8H), 2.71 (m, 4H), 1.48and 1.60 (2m, 6H)

HPLC: 91%

MS: MH⁺ 660/662

Stage 7:5-bromo-2-methoxy-4-[N-(4-phenylsulfanyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoicacid hydrochloride (22)

The product (108 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained at the previous stage.

Yield: 83%

MP: 158-166° C.

Elementary analysis calculated for C₃₃H₃₂BrN₃O₄S.1HCl.1H₂O: C, 56.54; H,5.03; N, 5.99. Found: C, 56.59; H, 4.96; N, 5.84.

HPLC: 95%

MS: MH⁺ 646/648

EXAMPLES 23 AND 244-[N-(4-benzenesulfonyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (23) and4-[N-(4-benzenesulfinyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (24) Stage 1: methyl4-[N-(4-benzenesulfonyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoateand methyl4-[N-(4-benzene-sulfinyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-5-bromo-2-methoxy-benzoate

To a solution of 100 mg of the obtained product of stage 6 of Example 22in 3 mL of dichloromethane is added an excess of metachloroperbenzoicacid (2 equivalents and 2 other equivalents over time) until totaldisappearance of the starting product (tracked by TLC). The reactioncrude production is filtered, the filtrate is washed with a saturatedsolution of sodium sulfite and then sodium bicarbonate. The collectedorganic phases are dried on magnesium sulfate and then evaporated underreduced pressure leading to a mixture which is purified by silica gelchromatography (petroleum ether/ethyl acetate 60:40). 35 mg of each ofthe esters are obtained—sulfonyl and sulfinyl forms respectively—.

Yield (sulfonyl): 33%

HPLC: 83%

MS: MH⁺ 692/694

Yield (sulfynyl): 34%

HPLC: 83%

MS: MH⁺ 676/778

Stage 2:4-[N-(4-benzenesulfonyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (23)

The product (20 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the sulfonylderivative obtained in the previous stage.

Yield: 55%

Elementary analysis calculated for C₃₃H₃₂BrN₃O₆S.0.75HCl: C, 56.15; H,4.68; N, 5.95. Found: C, 56.09; H, 4.65; N, 5.67.

HPLC: 84%

MS: MH⁺ 678/680

Stage 2:4-[N-(4-benzenesulfinyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (24)

The product (23 mg) is obtained as hydrochloride according to the methodof stage 6 of Example 2, by using as a substrate the sulfinyl obtainedin the previous stage.

Yield: 63%

Elementary analysis calculated for C₃₃H₃₂BrN₃O₅S.1HCl.1.5H₂O: C, 54.59;H, 5.00; N, 5.79. Found: C, 54.56; H, 4.91; N, 5.54.

HPLC: 85%

MS: MH⁺ 662/664

EXAMPLE 252-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoicacid hydrochloride (25) Stage 1: methyl2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl]-vinyl}-benzoate

The product (200 mg) is obtained according to the method of stage 3 ofExample 6, by using 150 mg of the hydrazine of Example 7 as a substrateand 125 mg of the acid of preparation 4 as co-substrate in the presenceof 102 mg of EDCI and 72 mg of HOBt in 1.5 mL of dimethylformamide.

Yield: 78%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 10.47 and 10.10 (2s broad, 1H), 7.95(m, 2H), 7.20-7.48 (m, 6H), 6.65-7.10 (m, 4H), 4.11 (2s, 6H), 3.98 (s,3H), 2.91 and 3.11 (m, 3H), 2.61 (m, 4H), 1.85 (m, 6H)

HPLC: 98%

MS: MH⁺ 530

Stage 2:2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoicacid hydrochloride (25)

The product (149 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 71%

Elementary analysis calculated for C₃₀H₃₃N₃O₅.1HCl.1.5H₂O: C, 62.22; H,6.44; N, 7.26. Found: C, 62.45; H, 6.34; N, 7.12.

HPLC: 94%

MS: MH⁺ 516

EXAMPLE 265-bromo-2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl]-vinyl}-benzoicacid hydrochloric (26) Stage 1: methyl5-bromo-2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoate

The product (234 mg) is obtained according the method of stage 3 ofExample 6, by using 120 mg of hydrazine of Example 7 as a substrate and134 mg of the acid of preparation 5 as a co-substrate in the presence of81 mg of EDCI and 57 mg of HOBt in 2 mL of dimethylformamide.

Yield: quantitative

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 10.37 and 9.95 (2s broad, 1H), 8.02 (m,2H), 7.00-7.29 (m, 5H), 6.43-6.88 (m, 4H), 3.95 (3s, 9H), 2.70 and 2.90(m, 3H), 2.40 (m, 4H), 1.60 (m, 6H)

HPLC: 87%

MS: MH⁺ 608/610

Stage 2:5-bromo-2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoicacid hydrochloride (26)

The product (217 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 86%

MP: 192-206° C.

Elementary analysis calculated for C₃₀H₃₂BrN₃O₅.1HCl.1H₂O: C, 55.52; H,5.44; N, 6.47. Found: C, 55.43; H, 5.51; N, 6.37.

HPLC: 91%

MS: MH⁺ 594/596

EXAMPLE 274-[N-(4-benzyl-phenyl)-[N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (27) Stage 1:(4-benzyl-phenyl)-(2-methyl-6-nitro-phenyl)-amine

The product (1.01 g) is obtained according to the method of stage 1 ofExample 4, by using 1.13 g of 2-fluoro-3-methyl-nitrobenzene and 2 g of4-benzyl-aniline in the presence of 1.31 g of potassium tert-butanolatein 30 mL of DMSO.

Estimated yield: 35% ¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.32 (s broad,1H), 7.96 (d, 2H), 6.68-7.51 (bulk aromatic, 10H), 3.93 (s, 2H), 2.06(s, 3H)

HPLC: 79%

MS: MH⁺ 319

Stage 2: N′-(4-benzyl-phenyl)-3-methyl-benzene-1,2-diamine

The product (530 mg) is obtained by hydrogenation according to themethod of stage 2 of Example 13.

Yield: 58%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.99-7.32 (bulk aromatic, 8H), 6.68 (d,2H), 6.52 (d, 2H), 3.89 (s, 2H), 2.18 (s, 3H)

Stage 3: (4-benzyl-phenyl)-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (460 mg) is obtained according the method of stage 3 ofExample 4, by using 525 mg of the previous derivative as a startingproduct, 247 μL of dibromopentane and 760 μL of DIPEA in 10 mL oftoluene.

Yield: 71%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.92-7.31 (bulk aromatic, 10H), 6.62(d, 2H), 6.17 (s broad, 1H), 3.90 (s, 2H), 2.72 (m, 4H), 2.10 (s, 3H),1.56 (m, 6H)

HPLC: 98%

MS: MH⁺ 357

Stage 4:N-(4-benzyl-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine (t)

The product (102 mg) is obtained according the method of stage 4 ofExample 1, by using 450 mg of the previous derivative as a startingproduct and 5.5 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced by 192 mg of lithium aluminiumhydride (4 equivalents) in 5 mL of tetrahydrofurane.

Estimated yield: 22%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.12-7.29 (bulk aromatic, 6H), 6.97(dd, 4H), 6.75 (d, 2H), 3.88 (s, 2H), 2.80 (m, 4H), 2.08 (s, 3H), 1.52(m, 6H)

HPLC: 64%

MS: MH⁺ 372

Stage 5: methyl4-[N-(4-benzyl-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoate

The product (91 mg) is obtained according to the method of stage 3 ofExample 6, by using 101 mg of the previous hydrazine and 91 mg of theacid of preparation 2 in the presence of 58 mg of EDCI and 41 mg of HOBtin 4 mL of dimethylformamide.

Yield: 51%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.97 and 9.79 (s broad, 1H), 7.97 (s,1H), 6.75-7.27 (bulk aromatic, 11H), 6.51 (d, 2H), 3.87 (s, 6H), 3.72(s, 4H), 2.74 (m, 2H), 2.37 (s, 3H), 2.36 (m, 2H), 1.40 (m, 6H)

HPLC: 96%

MS: MH⁺ 656/658

Stage 6:4-[N-(4-benzyl-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (27)

The product (74 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 84%

MP: 173-187° C.

Elementary analysis calculated for C₃₅H₃₆BrN₃O₄.1HCl.1H₂O: C, 60.31; H,5.64; N, 6.03. Found: C, 60.36; H, 5.62; N, 5.99.

HPLC: 98%

MS: MH⁺ 642/644

EXAMPLE 285-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (28) Stage 1:(4-bromo-phenyl)-(2-methyl-6-nitro-phenyl)-amine

The product (2.44 g) is obtained according to the method of stage 1 ofExample 4, by using 1.8 g of 2-fluoro-3-methyl-nitrobenzene and 3 g of4-bromo-aniline in the presence of 2.09 g of potassium tert-butanolatein 20 mL of DMSO.

Yield: 68%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.15 (s broad, 1H), 7.96 (d, 1H),7.07-7.51 (bulk aromatic, 4H), 6.61 (d, 2H), 2.09 (s, 3H)

HPLC: 90%

MS: MH⁺ 307/309

Stage 2: N²-(4-bromo-phenyl)-3-methyl-benzene-1,2-diamine

The product (2.2 g) is obtained according to the method of stage 2 ofExample 1, by using 2.44 g of the previous derivative as a startingproduct and 9 g of tin chloride hydrate in 30 mL of ethanol.

Yield: quantitative

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.22 (s, 1H), 7.02 (t, 1H), 6.45 (m,3H), 6.43 (d, 2H), 4.98 (s broad, 1H), 2.14 (s, 3H)

HPLC: 99%

MS: MH⁺ 277/279

Stage 3: (4-bromo-phenyl)-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (2 g) is obtained according to the method of stage 3 ofExample 4, by using 2.2 g of the previous derivative as a startingproduct, 1.08 mL of dibromopentane and 3.3 mL of DIPEA in 40 mL oftoluene.

Yield: 73%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.26 (m, 2H), 7.03 (t, 1H), 6.94 (d,2H), 6.56 (d, 2H), 6.14 (s broad, 1H), 2.70 (m, 4H), 2.10 (s, 3H), 1.55(m, 6H)

HPLC: 99%

MS: MH⁺ 345/347

Stage 4:(4′-methoxy-biphenyl-4-yl)-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (248 mg) is obtained according to the method of stage 4 ofExample 11, by using 300 mg of the previous derivative as a startingproduct, 198 mg of phenylboronic acid, 50 mg of palladium tetrakis, 110mg of lithium chloride in the presence of 2.17 mL of a 1 M calciumcarbonate solution in 6 mL of a methanol/toluene mixture (1:1).

Yield: 76%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.48 (d, 2H), 7.39 (d, 2H), 6.92-7.03(m, 5H), 6.74 (d, 2H), 6.24 (s broad, 1H), 3.84 (s, 3H), 2.74 (m, 4H),2.16 (s, 3H), 1.56 (m, 6H)

HPLC: 81%

MS: MH⁺ 373

Stage 5:N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine(u)

The product (92 mg) is obtained according to the method of stage 4 ofExample 1, by using 247 mg of the previous derivative as a startingproduct and 265 mg of sodium nitrite in 3 mL of acetic acid leading tothe nitroso intermediate which is reduced with 101 mg of lithiumaluminium hydride (4 equivalents) in 5 mL of tetrahydrofurane withreflux.

Yield: 35%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.48 (d, 2H), 7.38 (d, 2H), 7.17 (t,1H), 6.86-7.03 (m, 6H), 4.90 (s broad, 2H), 3.83 (s, 3H), 2.95 (m, 2H),2.69 (m, 2H), 2.11 (s, 3H), 1.51-1.66 (m, 6H)

HPLC: 95%

MS: MH⁺ 388

Stage 6: methyl5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoate

The product (24 mg) is obtained according to the method of stage 3 ofExample 6, by using 92 mg of the previous hydrazine and 79 mg of theacid of preparation 2 in the presence of 50 mg of EDCI and 35 mg of HOBtin 2.5 mL of dimethylformamide.

Yield: 15%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.00 (s, 1H), 6.85-7.51 (bulk aromatic,10H), 6.62 (d, 2H), 3.72-3.88 (m, 11H), 2.81 (m, 2H), 2.43 (m, 5H),1.25-1.56 (m, 6H)

HPLC: 87%

MS: MH⁺ 672/674

Stage 7:5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonylmethyl]-benzoicacid hydrochloride (28)

The product (13 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 52%

Elementary analysis calculated for C₃₅H₃₆BrN₃O₅.1HCl.1.5H₂O: C, 58.22;H, 5.58; N, 5.82. Found: C, 58.06; H, 5.63; N, 5.58.

HPLC: 82%

MS: MH⁺ 658/660

EXAMPLE 295-bromo-4-[N-cyano-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxybenzoic acid hydrochloride (29) Stage 1: tert-butylN-(2-methyl-6-nitro-phenyl)-hydrazino-carboxylate

To 250 mg of 2-fluoro-3-methyl-nitrobenzene in 5 mL of DMSO are added1.065 g of commercial tert-butoxycarbonylhydrazine (5 equivalents). Thewhole is brought to 100° C. for 10 min under microwave heating. Themedium is hydrolyzed and then extracted with ethyl acetate severaltimes. The organic phases are collected, dried on magnesium sulfate,filtered and evaporated under reduced pressure leading to a residuewhich is purified by chromatography on silica gel (cyclohexane/ethylacetate: 80/20). 342 mg of product corresponding to the expected productare obtained.

Yield: 80%

¹H NMR (CDCl₃, 250 MHz) δ (ppm): 7.86 (d, 1H), 7.35 (d, 1H), 6.97 (t,1H), 6.40 (s broad, 1H), 1.34 (s broad, 9H)

HPLC: 98%

Stage 2: tert-butylN-(4-cyano-phenyl)-N-(2-methyl-6-nitro-phenyl)-hydrazinocarboxylate

To 1.5 g of the product obtained in the previous stage in 10 mL ofdichloromethane are added at 0° C., 2.45 g of activated manganese oxide(5 equivalents). The whole is stirred at room temperature for 30 min,until complete disappearance of the starting product (tracked by TLC).The oxidized intermediate is filtered on celite, rinsed withdichloromethane and then concentrated under reduced pressure without anyother form of purification. The thereby obtained tert-butylazocarboxylate derivative is immediately taken up in 10 mL of methanolto which are successively added 1.27 g of 4-cyanophenylboronic acid (1.6equivalents) and 54 mg of copper acetate hydrate (0.05 equivalents). Thewhole is refluxed for 24 hrs until complete disappearance of theoxidized intermediate. The reaction medium is hydrolyzed and thenextracted with ethyl acetate several times. The organic phases arewashed with water, then with brine and finally dried on magnesiumsulfate, filtered and evaporated under reduced pressure. The obtainedresidue is purified by silica gel chromatography(dichloromethane/cyclohexane: 1/1) leading to 1.13 g of the expectedproduct.

Yield: 57%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.98 (d, 1H), 7.67 (t, 2H), 7.49 (m,3H), 6.60 (d, 2H), 2.49 (s, 3H), 1.48 (s, 9H)

HPLC: 78%

Stage 3: tert-butylN-(2-amino-6-methyl-phenyl)-N-(4-cyano-phenyl)-hydrazinocarboxylate

982 mg of the product are obtained by catalytic hydrogenation in thepresence of 110 mg of 5% palladium on charcoal in 50 mL of ethanol from1.13 g of the product obtained in the previous stage.

Yield: 97%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.48 (d, 2H), 7.09 (m, 1H), 6.62 (m,4H), 4.78 (s broad, 2H), 4.40 (s broad, 1H), 2.02 (s, 3H), 1.50 (s, 9H)

HPLC: 80%

Stage 4: tert-butylN-[2-(5-bromo-pentanoylamino)-6-methylphenyl]-N-(4-cyano-phenyl)-hydrazinocarboxylate

To 980 mg of the obtained product of the previous stage in 8 mL ofdichloromethane in the presence of 820 μL of DIPEA (2 equivalents) areadded dropwise and at room temperature 388 μL of 5-bromovalerylchloride. After 20 minutes, the reaction crude product hydrolyzed by a 1N hydrochloric acid solution is extracted with dichloromethane severaltimes. The organic phases are dried on magnesium sulfate, filtered andconcentrated under reduced pressure leading to 1.4 g of the expectedproduct.

Yield (estimation): 96%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 10.03 (s, 1H), 8.28 (d, 1H), 7.49 (d,1H), 7.34 (t, 2H), 6.95-7.20 (m, 3H), 3.43 (m, 2H), 3.30 (t, 2H), 2.51(t, 2H), 2.34 (m, 2H), 2.07 (s, 3H), 1.53 (s, 9H)

HPLC: 56%

Stage 5: tert-butylN-(4-cyano-phenyl)-N-[2-methyl-6-(2-oxo-piperidin-1-yl)-phenyl]-hydrazinocarboxylate

To 1.4 g of the obtained previous product in 5 mL of DMF are added 225mg of sodium hydride (2 equivalents) at 0° C. After 20 minutes at roomtemperature, the reaction crude product is hydrolyzed and then extractedwith ethyl acetate several times. The collected organic phases arewashed with water and then with brine and finally dried on magnesiumsulfate, filtered and concentrated under reduced pressure leading to 1.1g of the expected product.

Yield (estimation): quantitative

Stage 6: tert-butylN-[4-(amino-methyl)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarboxylate

To 440 mg of the product obtained from the previous stage in 3 mL of THFare added 493 μL of borane dimethylsulfide (5 equivalents). The whole isrefluxed for 1 hr. The reaction crude product is hydrolyzed andextracted with ethyl acetate several times. The organic phases arecollected, washed with water and then with a 1 N hydrochloric acidsolution. The aqueous phase is taken up with a saturated solution ofsodium bicarbonate and then extracted with ethyl acetate. The organicphases are collected, dried on magnesium sulfate, filtered andconcentrated under reduced pressure leading to 308 mg of the expectedproduct.

Yield (estimation): 71%

Stage 7: tert-butylN-[4-(acetylamino-methyl)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carboxylate

To a solution of 300 mg of the product obtained from the previous stagein 10 mL of tetrahydrofurane under an inert atmosphere are added 267 μLof DIPEA (2 equivalents) and 76 μL of acetic anhydride (1.4equivalents). The whole is stirred at room temperature for 30 minutesuntil complete disappearance of the starting product (tracked with TLC).The reaction medium taken up in ethyl acetate is hydrolyzed with a 1 Nhydrochloric acid solution and extracted several times. The aqueousphase is then taken up again with a sodium bicarbonate solution until apH of 8 and extracted with ethyl acetate. The organic phases arecollected, dried on magnesium sulfate, filtered and evaporated underreduced pressure. The obtained residue is purified by silica gelchromatography (ether and then dichloromethane) leading to 165 mg of theexpected product.

Yield (estimation): 51%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.92 (s broad, 1H), 7.18 (d, 1H), 7.07(m, 4H), 6.62 (d, 2H), 5.60 (s broad, 1H), 4.32 (m, 2H), 2.80 (m, 2H),2.65 (m, 2H) 2.31 (s, 3H), 2.01 (s, 3H), 1.60 (m, 6H), 1.44 (s, 9H)

Stage 8: methyl4-{N-[4-(acetylamino-methyl)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-5-bromo-2-methoxy-benzoate

To a solution of 51 mg of the acid obtained in preparation 2 (2equivalents) in 2 mL of dichloromethane are added 14.4 μL of oxalylchloride (2 equivalents) and 1 drop of dimethylformamide. The whole isstirred for 20 min at room temperature and then evaporated under reducedpressure. To the thereby obtained acid chloride, taken up again in 1 mLof acetonitrile, are successively added a solution of 38 mg of theprevious ester in 1 mL of acetonitrile and 1 mL of 4 N hydrochloric acidin dioxane. The whole is placed for 10 minutes under microwave heatingat 100° C. The reaction medium is hydrolyzed and then extracted withethyl acetate several times. The aqueous phase is then basified with a 1N soda solution and extracted with ethyl acetate and then withdichloromethane. The organic phases are collected, dried on magnesiumsulfate, filtered and then evaporated under reduced pressure. With asilica gel chromatography of the residue (dichloromethane/ethanol:98/2)18 mg of the expected product may be obtained.

Yield: 34%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 10.05 et 9.83 (2s broad, 1H), 7.99 (s,1H), 7.18 (m, 2H), 7.05 (m, 4H), 6.52 (d, 2H), 5.67 (s broad, 1H), 4.29(d, 2H), 3.88 (s, 3H), 3.73 (m,s, 2H), 3.71 (s, 3H), 2.75 (m, 2H), 2.40(m, 2H), 2.37 (s, 3H), 1.98 (s, 3H), 1.46 (m, 6H)

HPLC: 97.3%

MS: MH⁺ 637/639

Stage 9:4-{N-[4-(acetylamino-methyl)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl}-5-bromo-2-methoxy-benzoicacid hydrochloride (29)

The product (13.8 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained with the previous stage.

Yield: 75%

HPLC: 91%

MS: MH⁺ 623/625

EXAMPLE 304-[N-(4-benzoyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxybenzoic acid hydrochloride (30) Stage 1:(4-benzoyl-phenyl)-(2-nitro-phenyl)-amine

The product (770 mg) is obtained according to the method of stage 1 ofExample 4, by using 1.5 mL of 2-fluoro-nitrobenzene and 4.2 g of4-aminobenzophenone in the presence of 2.54 g of potassiumtert-butanolate in 40 mL of DMSO.

Yield: 17%

HPLC: 86%

MS: MH⁺ 319

Stage 2: N-(4-Benzoyl-phenyl)-benzene-1,2-diamine

The product (880 mg) is obtained according to the method of stage 2 ofExample 1, by using 770 mg of the previous derivative as a startingproduct and 2.73 g of tin chloride hydrate in 15 mL of ethanol.

Yield: quantitative

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.74 (t, 4H), 7.36-7.53 (m, 3H), 7.13(m, 2H), 6.70-6.85 (m, 4H), 5.63 (s broad, 1H), 3.80 (s broad, 1H)

HPLC: 82%

MS: MH⁺ 289

Stage 3: (4-benzoyl-phenyl)-(2-piperidin-1-yl-phenyl)-amine

The product (530 mg) is obtained according to the method of stage 3 ofExample 4, by using 697 mg of the previous derivative as a startingproduct, 330 μL of dibromopentane and 1.01 mL of DIPEA in 15 mL oftoluene.

Yield: 62%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.80 (dd, 4H), 7.45-7.56 (m, 4H),6.96-7.18 (m, 6H), 2.84 (m, 4H), 1.60-1.74 (m, 6H)

HPLC: 100%

MS: MH⁺ 357

Stage 4: N-(4-benzoyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine (v)

To a solution of 100 mg of the previous compound in 10 mL of DMF areadded 14 mg of sodium hydride (1.2 equivalents) and the whole is stirredat room temperature for 45 minutes. 2.3 mL of a freshly prepared 0.15 Msolution in monochloramine ether (1.2 equivalents) (J. Org. Chem. 2004,69, 1368-1371) is added. After 5 minutes, the medium is treated by asaturated solution of Na₂S₂O₃, taken up again with water and thenextracted with ether several times. The organic phases are dried onmagnesium sulfate, filtered and concentrated under reduced pressure. Theobtained residue is purified by silica gel chromatography (petroleumether/ethyl acetate: 95/5) leading to 75 mg of the expected product.

Yield: 72%

¹H NMR (CDCl₃, 250 MHz) δ (ppm): 7.73 (d, 4H), 7.48 (m, 3H), 7.25 (m,2H), 7.05-7.17 (m, 4H), 4.89 (s broad, 2H), 2.91 (m, 4H), 1.57 (m, 6H)

HPLC: 100%

MS: MH⁺ 372

Stage 5: methyl4-[N-(4-benzoyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoate

The product (83 mg) is obtained according to the method of stage 3 ofExample 6, by using 70 mg of the preceding hydrazine and 64 mg of theacid of preparation 2 in the presence of 41 mg of EDCI and 28 mg of HOBtin 1.5 mL of dimethylformamide.

Yield: 66%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.36 (s broad, 1H), 7.99 (s, 1H),6.80-7.76 (bulk aromatic, 14H), 3.89 (s, 3H), 3.80 (s, 2H), 3.72 (s,3H), 2.75 (m, 4H), 1.54 (m, 6H)

HPLC: 100%

MS: MH⁺ 656/658

Stage 6:4-[N-(4-benzoyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxybenzoic acid hydrochloride (30)

The product (31 mg) is obtained according to the method of stage 6 ofExample 2, by using as a substrate the product obtained in the previousstage.

Yield: 37%

Elementary analysis calculated for C₃₄H₃₂BrN₃O₅.1HCl.1.5H₂O: C, 57.84;H, 5.14; N, 5.95. Found: C, 58.04; H, 5.13; N, 5.55.

HPLC: 100%

MS: MH⁺ 642/644

EXAMPLE 315-bromo-4-[N-cyano-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxybenzoic acid hydrochloride (31) Stage 1: tert-butylN-(4-cyano-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarboxylate

To 280 mg of the product obtained in stage 5 of Example 29 in 2 mL oftetrahydrofurane are added 3.3 mL of a 1 M borane solution intetrahydrofurane (5 equivalents). The whole is refluxed for 3 hrs. Thereaction crude product is poured on a 1 N acid hydrochloric solution andextracted with ethyl acetate several times. The aqueous phase isbasified by a 1 N soda solution and extracted with dichloromethane. Thedifferent organic phases are collected, washed with water and then witha saturated solution of NaCl, dried on magnesium sulfate, filtered andconcentrated under reduced pressure. The obtained residue is purified bysilica gel chromatography (dichloromethane/ethyl acetate: 98/2) leadingto 82 mg of expected product.

Yield: 30%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 8.92 (s broad, 1H), 7.46 (d, 2H), 7.21(m, 1H), 7.06 (t, 2H), 6.72 (m, 2H) 2.74 (m, 4H), 2.29 (s, 3H), 1.60 (m,6H), 1.43 (s, 9H)

Stage 2: methyl5-bromo-4-[N-(4-cyano-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl]-2-methoxy-benzoate

The product (32 mg) is obtained according to the method of stage 8 ofExample 31, by using 42 mg of the product obtained in the previous stageas a substrate and 94 mg of the acid of preparation 2 as a co-substrate.

Yield: 56%

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 9.78 (s, 1H), 7.98 (s, 1H), 7.45 (d,2H), 7.24 (m, 2H), 7.01 (m, 2H), 6.62 (m, 2H), 3.88 (s, 2H), 3.37 (s,6H), 2.70 (m, 2H), 2.45 (m, 2H), 2.35 (s, 3H), 1.42 (m, 6H)

HPLC: 94%

MS: MH⁺ 591/593

Stage 3:5-bromo-4-[N-(4-cyano-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride (31)

The product (16.4 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 49%

HPLC: 98%

MS: MH⁺ 577/579

EXAMPLE 324-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (32) Stage 1:(4′-acetyl-biphenyl-4-yl)-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (1.35 g) is obtained according to the method of stage 4 ofExample 11, by using 2.6 g of the derivative obtained in stage 3 ofExample 28 as a starting product, 248 g of 4-acetyl-phenylboronic acid,307 mg of [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (II)and 4.58 g of cesium fluoride in 150 mL of dioxane.

Yield: 47%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.98 (d, 2H), 7.65 (d, 2H), 7.51 (d,2H), 7.03 (m, 3H), 6.76 (d, 2H), 6.29 (s broad, 1H), 2.75 (m, 4H), 2.63(s, 3H), 2.17 (s, 3H) 1.58 (m, 6H)

SM: MH⁺ 385

Stage 2:[4′-(2-methyl-[1,3]dithian-2-yl)-biphenyl-4-yl]-(2-methyl-6-piperidin-1-yl-phenyl)-amine

To a solution of 788 mg of the derivative obtained in the previous stagein 14 mL of dichloromethane are successively added 260 μL ofpropanedithiol (1.25 equivalents) and 380 μL of boron trifluoridecomplexed with diethyl ether. The whole is stirred for 2 days at roomtemperature until disappearance of the starting product. The reactionmedium is poured on a 2 N soda solution and then extracted withdichloromethane several times. The organic phases are washed with asaturated solution of sodium chloride, dried on sodium sulfate, filteredand concentrated under reduced pressure leading to 970 mg of theexpected product.

Yield: quantitative

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.96 (d, 2H), 7.58 (d, 2H), 7.48 (d,2H), 7.03 (m, 3H), 6.77 (d, 2H), 6.26 (s broad, 1H), 2.76 (m, 8H), 2.18(s, 3H), 1.95 (m, 2H), 1.84 (s, 3H), 1.54 (m, 6H)

Stage 3:N-[4′-(2-methyl-[1,3]dithian-2-yl)-biphenyl-4-yl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine(w)

The product (835 mg) is obtained according to the method of stage 4 ofExample 1, by using 970 mg of the previous derivative as a startingproduct and 1.11 g of sodium nitrite in 6 mL of acetic acid leading tothe nitroso intermediate which is reduced by 8.2 mL of a 1 M lithiumaluminium hydride solution in ether (4 equivalents) in 8 mL of etherwith reflux.

Yield: 83%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.92 (d, 2H), 7.57 (d, 2H), 7.46 (d,2H), 7.19 (d, 1H), 7.05 (t, 2H), 6.90 (d, 2H), 2.70-2.95 (m, 8H), 2.12(s, 3H), 1.96 (m, 2H) 1.82 (s, 3H), 1.65 (m, 6H)

Stage 4: methyl5-bromo-2-methoxy-4{N-[4′-(2-methyl-[1,3]dithian-2-yl)-biphenyl-4-yl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-benzoate

The product (637 mg) is obtained according to the method of stage 3 ofExample 6, by using 600 mg of the previous hydrazine and 406 mg of theacid of preparation 2 in the presence of 257 mg of EDCI and 181 mg ofHOBt in 4 mL of dimethylformamide.

Yield: 67%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 9.87 (s broad, 1H), 7.96 (m, 3H), 7.50(m, 5H), 7.20 (d, 1H), 7.03 (m, 2H), 6.65 (d, 2H), 3.88 (s, 3H), 3.70(2s, 5H), 2.75 (m, 8H), 2.44 (s, 3H), 1.97 (m, 2H), 1.81 (s, 3H),1.25-1.55 (m, 6H)

MS: MH⁺ 774/776

Stage 5: methyl4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-5-bromo-2-methoxy-benzoate

To a solution of 30 mg of the derivative obtained in the previous stagein 100 μL of a tetrahydrofurane/water mixture (1:1) are successivelyadded 17 mg of mercury(II) oxide (2 equivalents) and 10 μL of borontrifluoride complexed with ether (2 equivalents). The whole is stirredat room temperature for 1 hour, until disappearance of the startingproduct. The reaction medium is poured in a 2 M soda bicarbonatesolution and then extracted with ethyl acetate several times. Theorganic phases are washed with a saturated solution of sodium chloride,dried on sodium sulfate, filtered and concentrated under reducedpressure. Silica gel chromatography (cyclohexane/ethyl acetate: 70/30)is able to isolate 19.5 mg of the desired product.

Yield: 73%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 9.88 (s broad, 1H), 7.97 (m, 3H), 7.62(d, 2H), 7.48 (d, 2H), 7.21 (d, 1H), 7.03 (m, 2H), 6.67 (d, 2H), 3.89(s, 3H), 3.77 (2s, 5H), 2.80 (m, 2H), 2.62 (s, 3H), 2.42 (m+s, 5H),1.30-1.50 (m, 6H)

MS: MH⁺ 684/686

Stage 6:4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride (32)

The product (115 mg) is obtained as a hydrochloride form according tothe method of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 34%

¹H NMR (DMSO, 400 MHz) δ (ppm): 7.99 (m, 3H), 7.37-7.81 (m, 7H), 7.37(s, 1H), 6.78 (m, 2H), 4.24 (d, 1H), 4.03 (d, 1H), 3.79 (s, 3H),3.20-3.60 (m, 4H), 2.57 (s, 3H), 2.28 (s, 3H), 1.51-1.86 (m, 6H)

HPLC: 96%

MS: MH⁺ 670/672

EXAMPLE 335-bromo-2-methoxy-4-[N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (33) Stage 1:(4-bromo-3-methyl-phenyl)-(2-methyl-6-nitro-phenyl)-amine

The product (3.90 g) is obtained according to the method of stage 1 ofExample 4, by using 2.78 g of 2-fluoro-3-methyl-nitrobenzene and 5 g of4-bromo-3-methyl-aniline in the presence of 3.22 g of potassiumtert-butanolate in 70 mL of DMSO.

Yield: 68%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 8.15 (s broad), 7.96 (d, 1H), 7.43 (d,1H), 7.37 (m, 1H), 7.10 (t, 1H), 6.65 (m, 1H), 6.42 (dd, 1H), 2.33 (s,3H), 2.10 (s, 3H)

Stage 2: N²-(4-bromo-3-methyl-phenyl)-3-methyl-benzene-1,2-diamine

The product (3.2 g) is obtained according to the method of stage 2 ofExample 1, by using 3.9 g of the previous derivative as a startingproduct and 13.7 g of tin chloride hydrate in 60 mL of ethanol.

Yield: 90%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.29 (d, 1H), 7.03 (t, 1H), 6.68 (d,2H), 6.47 (d, 1H), 6.28 (dd, 1H), 4.94 (s broad, 1H), 2.29 (s, 3H), 2.16(s, 3H)

Stage 3:(4-bromo-3-methyl-phenyl)-(2-methyl-6-piperidin-1-yl-phenyl)-amine

The product (3.21 g) is obtained according to the method of stage 3 inExample 4, by using 3.2 g of the previous derivative as a startingproduct, 1.50 mL of dibromopentane and 4.30 mL of DIPEA in 50 mL oftoluene.

Yield: 81%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.28 (d, 1H), 7.04 (m, 3H), 6.58 (d,1H), 6.41 (dd, 1H), 6.13 (s broad, 1H), 2.72 (m, 4H), 2.32 (s, 3H), 2.11(s, 3H), 1.57 (m, 6H)

Stage 4:(4′-methoxy-2-methyl-biphenyl-4-yl)-(2-methyl-6-piperidin-1-yl-phenyl-amine

The product (1.921 g) is obtained according to the method of stage 4 ofExample 11, by using 3 g of the previous derivative as a startingproduct, 1.904 g of 4-methoxy-phenyl boronic acid, 392 mg of palladiumtetrakis, 1.062 g of lithium chloride in the presence of 9 mL of a 1 Msodium carbonate solution in 60 mL of a methanol/toluene mixture (1:1).

Yield: 60%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.28 (d, 2H), 7.03 (m, 6H), 6.59 (m,2H), 6.26 (s broad, 1H), 3.86 (s, 3H) 2.77 (m, 4H), 2.25 (s, 3H), 2.20(s, 3H), 1.63 (m, 6H)

Stage 5:N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine(x)

The product (385 mg) is obtained according to the method of stage 4 ofExample 1, by using 490 mg of the previous derivative as a startingproduct and 515 mg of sodium nitrite in 4 mL of acetic acid leading tothe nitroso intermediate which is reduced with 4.8 mL of a 1 M lithiumaluminium hydride solution in ether (4 equivalents) in 4.5 mL of etherwith reflux.

Yield: 80%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 6.90-7.27 (bulk aromatic, 10H), 6.78 (sbroad, 1H), 6.57 (d, 1H), 3.83 (s, 3H), 2.92 (m, 4H), 2.22 (s, 3H), 2.12(s, 3H), 1.68 (m, 4H), 1.53 (m, 2H)

Stage 6: methyl5-bromo-2-methoxy-4-[N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoate

The product (450 mg) is obtained according to the method of stage 3 ofExample 6, by using 381 mg of the previous hydrazine and 316 mg of theacid of preparation 2 in the presence of 200 mg of EDCI and 144 mg ofHOBt in 3.8 mL of dimethylformamide.

Yield: 69%

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 10.06 et 9.84 (2 s broad, 1H), 8.01 (s,1H), 7.20 (m, 4H), 6.89-7.02 (m, 5H), 6.50 (s, 1H), 6.38 (d, 1H), 3.89(s, 3H), 3.84 (s, 3H), 3.76 (m, 2H), 3.72 (s, 3H), 2.80 (m, 2H), 2.45(m, 5H), 2.18 (s, 3H), 1.30-1.58 (m, 6H)

Stage 7:5-bromo-2-methoxy-4-[N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride (33)

The product (264 mg) is obtained as a hydrochloride according to themethod of stage 6 of Example 2, by using as a substrate the productobtained in the previous stage.

Yield: 67%

¹H NMR (DMSO, 200 MHz) δ (ppm): 11.79 (s broad, 1H), 11.44 (s broad,1H), 7.96 (d, 1H), 7.81 (s, 1H), 7.70 (m, 2H), 7.34 (s, 1H), 7.23 (d,2H), 6.99 (d, 1H), 6.75 (d, 2H), 6.44 (s, 1H), 6.42 (d, 1H), 4.10 (m,2H), 3.78 (s, 6H), 3.40 (m, 4H), 2.27 (s, 3H), 2.19 (s, 3H), 1.53-1.86(m, 6H)

HPLC: 98.5%

MS: MH⁺ 672/674

Results of Biological Activity

Activity of molecules against the papilloma virus may be evaluated indifferent in vitro and cell tests such as those described by Chiang etal. (1992), Proc. Natl. Acad. Sci. USA, 89: 5799-5803 or further byWhite et al. (2003), Journal of Biological Chemistry, 278: 26765-26772.

EXAMPLE 34 Pharmacological Studies of the Compounds of the Invention inCell Tests for Replication of Viral DNA of HPVs

These tests measure replication of viral genomic DNA in human cells.They are based on co-transfection of a reporter vector containing aviral replication origin (ori) and of expression vectors coding for theE1 and E2 proteins of HPV. With them, it is possible to follow the wholeof the biological functions of E1 and E2 required for replicating theHPV genome.

A reporter ‘replicon’ vector containing the viral replication origin ofHPV11/HPV6 (also called LCRs which bear sites for binding the E1 and E2proteins of HPV) and the gene coding for firefly luciferase under thetranscriptional control of the SV40 promoter were built. It was checkedthat the presence of the HPV replication origin does not have anytranscriptional effect on expression of the gene of luciferase, this inthe presence or in the absence of viral E1 or E2 proteins.Co-transfection of this replicon vector and of vectors for expressingHPV E1 and E2 proteins leads to an increase in luciferase activitydepending on the presence of E1 and E2 and expresses the increase in thenumber of reporter vectors. This is due to the activity of the viral E1and E2 proteins which allow replication, in mammal cells, of thisreplicon vector containing a viral replication origin.

The chemical compounds were evaluated for their activity inhibitingviral replication dependent on E1 and E2 of HPV11/HPV6 in these celltests by co-transfecting, in human cell lines derived from kidneyepithelial or cervical carcinoma cells, the replicon-reporter vector andpairs of HPV11/HPV6 E1 and E2 expression vectors. Various doses of thecompounds were incubated for 2-6 days after transfection in the cellmedium and luciferase activity was determined by means of a luminometerin order to evaluate IC₅₀ of the compounds on replication of the HPVgenome.

All the compounds shown in the examples above inhibit replicationdependent on E1 and E2 of HPV11/HPV6 in cells with an IC₅₀ less than 20μM. The preferred compounds are those for which IC₅₀ may be less than750 nM.

With complementary cell tests, it was possible to show that thecompounds shown in the examples above inhibit HPV11 and HPV6 E1/E2interaction.

1.-15. (canceled)
 16. Compounds of formula (I):

as well as their stereoisomers, wherein G₁ represents a bond or asaturated or unsaturated, branched or linear hydrocarbon chaincomprising 1-4 carbon atoms, optionally substituted with one or twoalkyl groups, G₂ represents a

 group, wherein: R represents hydrogen atom, an alkyl, haloalkyl group,or a pro-drug radical G represents a bond or a saturated or unsaturated,linear or branched hydrocarbon chain comprising 1-4 carbon atoms,optionally substituted with one or two alkyl groups, W represents anoxygen, sulfur atom or NH, R₁ and R₂ either identical or different, eachrepresent a group selected from a hydrogen atom, a halogen atom, ahydroxyl, thio, alkoxy, haloalkoxy, alkylthio, haloalkylthio, amino,monoalkylamino, dialkylamino, cycloalkyl, alkyl or haloalkyl group, R₃represents an acid group or a pro-drug radical of the acid function orelse a bioisoster of the acid function A represents an aryl, cycloalkyl,cycloalkenyl group or a heterocycle, each optionally substituted, and Brepresents an aryl group or a 6-membered heterocycle, each optionallysubstituted, as well as their pharmaceutically acceptable salts.
 17. Thecompounds according to claim 16, wherein R represents hydrogen atom, analkyl, haloalkyl group, or a pro-drug radical chosen among a carbamate,acetyl, dialkylaminomethyl or —CH₂—O—CO-Alk,
 18. The compounds accordingto claim 16, wherein the pro-drug radical of the acid function is anester.
 19. The compounds according to claim 16, wherein the bioisosterof the acid function is a tetrazole, phosphonate, phosphonamide,sulfonate or sulfonamide,
 20. The compounds according to claim 16,wherein A is substituted with one or two groups, either identical ordifferent, selected from: a hydrogen atom, a halogen atom, an alkoxy,alkylthio, haloalkoxy, haloalkylthio, hydroxyl, thio, cyano, amino,monoalkylamino, or dialkylamino group, an —SO_(n)R′, —COR′, —CO₂R′,—OCOR′, —CONR′R″, —NR′COR″ or —NRSO₂R″ group, wherein R′ and R″ eachrepresent independently of each other an hydrogen atom, an alky,haloalkyl group, and n has the value 1 or 2, an alkyl or haloalkylgroup, the alkyl group being optionally substituted with a cyano, amino,monoalkylamino, dialkylamino or acylamino group, an aryl, arylalkyl,—X-aryl, —X-arylalkyl or -Alk-X-aryl group wherein X represents —O—,—NH—, —N(Alk), —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—, eachsubstituted on the aryl portion with one or two substituents, eitheridentical or different, selected from: a hydrogen atom or an halogenatom, an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino ordialkylamino, acid, ester, amide, mono- or di-alkylamide group, an—SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or —NR′SO₂R″ group,wherein R′ and R″ each represent independently of each other a hydrogenatom, an alkyl, haloalkyl group and n has the value 1 or 2, aheterocycle, -Alk-heterocycle, —X-heterocycle, —X-Alk-heterocycle, or-Alk-X-heterocycle group, wherein X represents —O—, —NH—, —N(Alk)-,—N(COCH₃)—, —S—, —SO—, —SO₂—, —CO—, or —CONH—, each optionallysubstituted on the heterocycle portion with one or two substituentseither identical or different, selected from: V a hydrogen atom or ahalogen atom, an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino ordialkylamino, acid, ester, amide, mono- or di-alkylamide group, or—SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or NR′SO₂R″ group,wherein R′ and R″ each represent independently of each other a hydrogenatom, an alkyl, haloalkyl group and n has the value 1 or 2, acycloalkyl, -Alk-cycloalkyl, cycloalkenyl, -Alk-cycloalkenyl,—X-cycloalkyl, —X-Alk-cycloalkyl, —X-cycloalkenyl, —X-Alk-cycloalkenyl,-Alk-X-cycloalkyl, -Alk-X-cycloalkenyl group, wherein X represents —O—,—NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH— eachoptionally substituted on the cyclic portion with one or twosubstituents, either identical or different, selected from: a hydrogenatom or a halogen atom, an alkyl, haloalkyl, alkoxy, haloalkoxy, thio,alkylthio, haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylaminoor dialkylamino, acid, ester, amide, mono- or di-alkylamide, or oxo or—SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or NR′SO₂R″ group,wherein R′ and R″ each represent independently of each other a hydrogenatom, an alkyl, haloalkyl group and n has the value 1 or
 2. 21.Compounds according to claim 16, wherein B is an aryl or 6-memberedheterocycle, substituted in the ortho position with a R₄ group andoptionally substituted with a R₅ group, wherein: R₄ represents: analkyl, —NHAlk, —NAlkAlk′, —NHcycloalkyl or —NAlkcycloalkyl group, Alkand Alk′ being identical or different, a cycloalkyl, cycloalkenyl,N-cycloalkyl or N-cycloalkenyl group, each optionally substituted withone or two substituents, either identical or different, selected from ahydrogen atom, a halogen atom, an alkyl, haloalkyl, alkoxy, haloalkoxy,thio, alkylthio, haloalkylthio, hydroxyl, cyano, acyl, amino,monoalkylamino or dialkylamino, acid, ester, amide, mono- ordialkylamide, oxo or —X-aryl group and wherein X represents —O—, —NH—,—N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—, or an aryl groupoptionally substituted with one or two substituents, either identical ordifferent, an hydrogen atom, an halogen atom, an alkyl, haloalkyl,alkoxy, haloalkoxy, thio, alkylthio, haloalkylthio, hydroxyl, cyano,acyl, amino, monoalkylamino or dialkylamino, acid, ester, amide, mono ordialkylamide or —X-aryl group, wherein X represents —O—, —NH—, —N(Alk)-,—N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—, R₅ represents: a hydrogenatom or a halogen atom, a hydroxyl, alkoxy, haloalkoxy, thio, alkylthio,haloalkylthio, amino, monoalkylamino, dialkylamino, —NHacyl, cyano,acyl, acid, ester, amide, monoalkylamide or dialkylamide group, an alkylor haloalkyl group, the alkyl group may be substituted with a cyano,hydroxyl, alkoxy, acid or ester group, a —SO_(n)Alk, —SO_(n)NH₂,—SO_(n)NHAlk or —SO_(n)NAlkAlk′ group, wherein n has the value of 1 or 2and Alk and Alk′ are either identical or different, or a piperidine,oxopiperidine, morpholine group, or else a piperazine group optionallysubstituted with an alkyl or acyl group.
 22. Compounds according toclaim 16, wherein: G₁ represents a bond or a saturated or unsaturated,linear or branched hydrocarbon chain comprising 1-4 carbon atoms,optionally substituted with one or two alkyl groups, G₂ represents a

 group, wherein: R represents an hydrogen atom, an alkyl, haloalkylgroup, or a pro-drug radical G represents a bond or a saturated orunsaturated, linear or branched, hydrocarbon chain comprising 1-4 carbonatoms, optionally substituted with one or two alkyl groups, and Wrepresents an oxygen, sulphur atom or NH, R₁ and R₂ either identical ordifferent, each represent a group selected from a hydrogen atom, ahalogen atom, a hydroxyl, thio, alkoxy, haloalkoxy, alkylthio,haloalkylthio, amino, monoalkylamino, dialkylamino, cycloalkyl, alkyl orhaloalkyl group, R₃ represents an acid group or a pro-drug radical ofthe acid function or else a bioisoster of the acid function A representsan aryl or heterocycle group, each optionally substituted with one ortwo groups, either identical or different, selected from: a hydrogenatom, a halogen atom, an alkoxy, alkylthio, haloalkoxy, haloalkylthio,hydroxyl, thio, cyano, amino, monoalkylamino or dialkylamino group, a—SO_(n)R′, —COR′—, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or —NR′SO₂R″group, wherein R′ and R″ each represent independently of each other anhydrogen atom, an alkyl, haloalkyl group, and n has the value 1 or 2, analkyl or haloalkyl group, the alkyl group being optionally substitutedwith a cyano, amino, monoalkylamino, dialkylamino or acylamino group, anaryl, arylalkyl, —X-aryl group, wherein X represents —O—, —NH—,—N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH— group, eachsubstituted on the aryl portion with one or two substituents, eitheridentical or different, selected from: an hydrogen atom or an halogenatom, an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino ordi-alkylamino, acid, ester, amide, mono- or dialkylamide group, or a—SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or —NR′SO₂R″ group,wherein R′ and R″ each represent independently of each other an hydrogenatom, an alkyl, haloalkyl group, and n has the value 1 or 2, aheterocycle, —X-heterocycle group wherein X represents —O—, —NH—,—N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—, each optionallysubstituted on the heterocycle portion with one or two substituents,either identical or different, selected from: a hydrogen atom or ahalogen atom, an alkyl, haloalkyl, alkoxy, haloalkoxy, thio, alkylthio,haloalkylthio, hydroxyl, cyano, acyl, amino, monoalkylamino ordialkylamino, acid, ester, amide, mono- or di-alkylamide group, or an—SO_(n)R′, —COR′, —CO₂R′, —OCOR′, —CONR′R″, —NR′COR″ or —NR′SO₂R″ group,wherein R′ and R″ each represent independently of each other a hydrogenatom, an alkyl, haloalkyl group, and n has the value 1 or 2, or acycloalkyl, cycloalkenyl, —X-cycloalkyl, —X-cycloalkenyl group wherein Xrepresents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or—CONH— group, each optionally substituted on the cyclic portion with oneor two substituents, either identical or different, selected from: ahydrogen atom or a halogen atom, an alkyl, haloalkyl, alkoxy,haloalkoxy, thio, alkylthio, haloalkylthio, hydroxyl, cyano, acyl,amino, monoalkylamino or dialkylamino, acid, ester, amide, mono- ordi-alkylamide, or oxo group, or an —SO_(n)R′, —COR′, —CO₂R′, —OCOR′,—CONR′R″, —NR′COR″ or —NR′SO₂R″ group, wherein R′ and R″ each representindependently of each other a hydrogen atom, an alkyl, haloalkyl group,and n has the value 1 or 2, and B represents a phenyl or pyridine group:substituted in the ortho position with an N-cycloalkyl group or with acyclohexyl, each optionally substituted with one or two substituents,either identical or different, selected from a hydrogen atom, an alkyl,haloalkyl, alkoxy, haloalkoxy, —X-aryl group, where X represents —O—,—NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—, —CO— or —CONH—, and/oroptionally substituted with a halogen atom or with an alkyl or haloalkylgroup.
 23. Compounds according to claim 22, wherein B represents aphenyl or pyridine group: substituted in the ortho position with apiperidine group or with a cyclohexyl, each optionally substituted withone or two substituents, either identical or different, selected from ahydrogen atom, an alkyl, haloalkyl, alkoxy, haloalkoxy, —X-aryl group,where X represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—, —SO—, —SO₂—,—CO— or —CONH—, and/or optionally substituted with a halogen atom orwith an alkyl or haloalkyl group.
 24. Compounds according to claim 16,wherein: G₁ represents a bond or a saturated or unsaturated, linear orbranched hydrocarbon chain comprising 1-4 carbon atoms, optionallysubstituted with one or two alkyl groups, G₂ represents a

 group, wherein n is an integer comprised between 1 and 4 and m is aninteger having the value 1 or 2, R₁ represents an alkoxy group, R₂represents a hydrogen or halogen atom, or an alkyl group, R₃ representsan acid or ester group, A represents an aryl group optionallysubstituted: in the meta or para position with: a halogen atom or analkyl, haloalkyl, cyano, alkoxy, haloalkoxy, acylaminoalkyl group or an—XR group, wherein X represents —O—, —NH—, —N(Alk)-, —N(COCH₃)—, —S—,—SO—, —SO₂—, —CO— or —CONH— group, and R represents an arylalkyl,cycloalkyl or aryl group, each optionally substituted with one or twosubstituents, either identical or different, chosen among a halogenatom, an alkoxy, alkyl, haloalkyl, cyano, acyl, amino, monoalkylamino ordialkylamino, acid, ester, amide, mono- or di-alkylamide group, or a—SO_(n)R′, —OCOR′, —NR′COR″ or —NR′SO₂″ group, wherein R′ and R″ eachrepresent independently of each other a hydrogen atom, an alkyl,haloalkyl group, and n has the value 1 or 2, a cycloalkyl, aryl,arylalkyl group or heterocycle, each being optionally substituted withone or two substituents, either identical or different, chosen among ahalogen atom, an alkoxy, alkyl, haloalkyl, cyano, acyl, amino,monoalkylamino or dialkylamino, acid, ester, amide, mono- ordi-alkylamide group, or a —SO_(n)R′, —OCOR′, —NR′COR″, or —NR′SO₂R″group, wherein R′ and R″ each represent independently of each other ahydrogen atom, an alkyl, haloalkyl group and n has the value 1 or 2,and/or in the ortho or meta position with an alkyl group, and Brepresents an aryl group, substituted in the ortho position with aheterocycle, and/or substituted in the ortho′ position with an alkylgroup.
 25. Compounds according to claim 16, wherein: G₁ represents abond or a saturated or unsaturated, linear or branched hydrocarbon chaincomprising 1-4 carbon atoms, optionally substituted with one or twoalkyl groups, G₂ represents a

 group, wherein n is an integer comprised between 1 and 4 and m is aninteger having the value 1 or 2, R₁ represents an alkoxy group, R₂represents a hydrogen or halogen atom, or an alkyl group, R₃ representsan acid or ester group, A represents an aryl group optionallysubstituted: in the meta or para position with: a halogen atom or acyano, alkoxy, haloalkoxy, acylaminoalkyl or —XR group, wherein Xrepresents —O—, —S—, —SO—, —SO₂—, or —CO— and R represents an arylalkyl,cycloalkyl or aryl group, each optionally substituted with one or twosubstituents, either identical or different, chosen among a halogenatom, an alkoxy or acyl group, or a cycloalkyl, aryl or arlyalkyl group,each optionally substituted with one or two substituents, eitheridentical or different, chosen among an acyl or alkoxy group, and and/orin the ortho or meta position with an alkyl group, and B represents anaryl group, substituted in the ortho position with a heterocycle, and/orsubstituted in the ortho′ position with an alkyl group.
 26. Compoundsaccording to claim 24, wherein G₁ represents a bond or a hydrocarbonchain comprising 1 or 2 carbone atoms.
 27. Compounds according to claim24, wherein n has the value 1 or
 2. 28. Compounds according to claim 24,wherein R₁ is in the ortho position relatively to R₃.
 29. Compoundsaccording to claim 24, wherein R₂ is in the meta position relatively toR₃.
 30. Compounds according to claim 24, wherein B represents an arylgroup, substituted in the ortho position with a piperidine group, and/orsubstituted in the ortho′ position with an alkyl group.
 31. Compoundsaccording to claim 16, wherein the said compounds are selected from thefollowing group: 1) 5-bromo-2-methoxy-4-[N4-methoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 2)5-bromo-2-methoxy-4-[N-(2-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 3)5-bromo-2-methoxy-4-[N-(3-methoxy-benzyl)-N-(2-piperidin-1-yl-phenylhydrazinocarbonylmethyl]-benzoic acid hydrochloride 4)4-[N-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 5)5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoicacid hydrochloride 6)5-bromo-2-methoxy-{N-[2-(4-methoxy-phenyl)-ethyl]-N-2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-benzoicacid hydrochloride 7)5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methylpiperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoicacid hydrochloride 7a) Methyl5-bromo-2-methoxy-4-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl-methyl]-benzoate8)5-bromo-2-methoxy-4-[N-(4-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 9)5-bromo-4-[N-(4-cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride 10)5-bromo-2-methoxy-4-[N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazino-carbonylmethyl]-benzoicacid hydrochloride 11)5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 12)5-bromo-4-[N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride 13)5-bromo-2-methoxy-4-[N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 14)5-bromo-4-{N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoicacid hydrochloride 15)4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methylpiperidin-1-yl-phenyl)-hydrazinocarbonylmethyl}-2-methoxy-benzoicacid hydrochloride 16)5-bromo-4-{N-[4-fluoro-phenoxy)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl}-2-methoxy-benzoicacid hydrochloride 16a) Methyl5-bromo-4-{N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methylpiperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl}-2-methoxy-benzoate17) 4-[N-(4-benzyl-phenyl)-N-(2-piperidin-1-yl-phenyl)hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoic acid hydrochloride18) 4-[N-(4-bromo-phenyl)-N-(2-piperidin-1-yl-phenyl)hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoic acid hydrochloride19)4-[N-(3′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride 20)4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-chloro-2-methoxy-benzoicacid hydrochloride 21)5-bromo-2-methoxy-4-[N-(3-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 22)5-bromo-2-methoxy-4-[N-(4-phenylsulfanyl)-phenyl]-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride 23)4-[N-(4-benzenesulfonyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 24)4-[N-(4-benzenesulfinyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 25)2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoicacid hydrochloride 26)5-bromo-2-methoxy-4-{(E)-2-[N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonyl]-vinyl}-benzoicacid hydrochloride 27)4-[N-(4-benzyl-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 28)5-bromo-2-methoxy-4-[N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazino-carbonyl-methyl]-benzoicacid hydrochloride 29)4-[N-(acetylamino-methyl)-phenyl]-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 30)4-[N-(4-benzoyl)-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 31)5-bromo-4-[N-(4-cyano-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-2-methoxy-benzoicacid hydrochloride 32)4-[N-(4′-acetyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-5-bromo-2-methoxy-benzoicacid hydrochloride 33)5-bromo-2-methoxy-4-[N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinocarbonylmethyl]-benzoicacid hydrochloride.
 32. Intermediates for the synthesis of compoundsaccording to claim 31 selected from the following group: a)N-(4-methoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine b)N-(2-piperidin-1-yl-phenyl)-N-(4-trifluoromethoxy-phenyl)-hydrazine c)N-(3-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine d)N-(4-benzyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine e)N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine f)N-[2-(4-methoxy-phenyl)-ethyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine g)N-(4-methoxy-phenyl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine h)N-(4-methoxy-benzyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine i)N-(4-cyclohexyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine j)N-(2-methyl-6-piperidin-1-yl-phenyl)-N-(4-trifluoro-methoxy-phenyl)-hydrazinek) N-(4′-methoxy-biphenyl-4-yl)-N-(2-piperidin-1-yl-phenyl)-hydrazine l)N-(4-cyclohexyloxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine m)N-(4-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine n)N-[4-(4-chloro-phenoxy)-phenyl]-N-(2-piperidin-1-yl-phenyl)-hydrazine o)N-[4-(4-fluoro-phenoxy)-phenyl]-N-(2-methylpiperidin-1-yl-phenyl)-hydrazinep) N-(4-benzyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine q)N-(4-bromo-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine r)N-(3-phenoxy-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine s)N-(4-phenylsulfanyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine t)N-(4-benzyl-phenyl)-N-(2-methylpiperidin-1-yl-phenyl)-hydrazine u)N-(4′-methoxy-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazinev) N-(4-benzoyl-phenyl)-N-(2-piperidin-1-yl-phenyl)-hydrazine w)N-[4′-(2-methyl-[1,3]dithian-2-yl)-biphenyl-4-yl]-N-(2-methylpiperidin-1-yl-phenyl)-hydrazinex)N-(4′-methoxy-2-methyl-biphenyl-4-yl)-N-(2-methyl-6-piperidin-1-yl-phenyl)-hydrazine.33. A method for preparing compounds of formula (I) according to claim16, in which G₂ represents the

 radical, wherein the following steps are carried out: 1) Reaction ofthe hydrazine function of a compound of formula (II)

wherein A, B and G₁ are as defined in claim 16, with the acid functionof a compound of formula (III)

wherein R₁, R₂ and G are as defined in claim 16, and P represents agroup protecting the acid function, in order to obtain the compound offormula (IV)

2) Deprotection of the —CO₂P group of the compound of formula (IV) byhydrolysis in order to obtain the compound of formula (I)

wherein W represents an oxygen atom and R₃ is as defined in claim 16, 3)If necessary, reaction of the compound of formula (I) obtained in step2) or else of the compound of formula (IV) obtained in step 1) with aLawesson reagent, so that a compound of formula (I) may be obtained,wherein W represents a sulphur atom.
 34. A method for preparingcompounds of formula (I) according to claim 16, in which G₂ representsthe

 radical, wherein the following steps are carried out: 1) Reaction in anacid medium of the compound of formula (V):

wherein R₁, R₂ and G are as defined in claim 16, and P represents agroup protecting the acid function, on a compound of formula (XXIV)

wherein A, B and G₁ are as defined in claim 16, in order to obtain thecompound of formula (IV):

2) Deprotection of the —CO₂P group of the compound of formula (IV) byhydrolysis in order to obtain the compound of formula (I)

wherein W represents an oxygen atom and R₃ is as defined in claim 16.35. A pharmaceutical composition comprising at least one compound offormula (I) according to claim 16, in association with apharmaceutically acceptable excipient.
 36. A method for treating orpreventing an infection by the papilloma virus comprising theadministration of an efficient quantity of a compound according to claim16 to a patient in need thereof
 37. The method according to claim 36,wherein the said method is intended for treating or preventing lesionsand diseases associated with infections by the papilloma virus.
 38. Themethod according to claim 36, wherein the said method is intended fortreating or preventing ano-genital warts, laryngeal, conjunctive orbuccal papillomas or other epithelial lesions
 39. The method accordingto claim 38, wherein the said ano-genital warts are acuminatedcondylomas or plane condylomas.
 40. The method according to claim 39,wherein the said other epithelial lesions are recurrent respiratorypapillomatoses and low grade and high grade intra-epithelial neoplasias,bowenoid papuloses, warts, epidermodysplasia verruciformis, carcinomas,and all lesions associated with the papilloma virus.
 41. The methodaccording to claim 40, wherein the said warts are verruca vulgaris,verruca plantaris, myrmecia wart, surface wart or verruca plana.
 42. Themethod according to claim 40, wherein the said carcinomas are anygenital carcinomas.